Colorectal cancer is a disease in which malignant (cancer) cells form in the tissues of the colon or the rectum.

The colon is part of the body’s digestive system. The digestive system removes and processes nutrients (vitamins, minerals, carbohydrates, fats, proteins, and water) from foods and helps pass waste material out of the body. The digestive system is made up of the mouth, throat, esophagus, stomach, and the small and large intestines. The colon (large bowel) is the first part of the large intestine and is about 5 feet long. Together, the rectum and anal canal make up the last part of the large intestine and are 6 to 8 inches long. The anal canal ends at the anus (the opening of the large intestine to the outside of the body).

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Cancer that begins in the colon is called colon cancer, and cancer that begins in the rectum is called rectal cancer. Cancer that affects either of these organs may also be called colorectal cancer.

Other PDQ summaries containing information related to colorectal cancer include:

Colorectal cancer is the second leading cause of death from cancer in the United States.

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer death in the United States when numbers for men and women are combined. Between 2012 and 2021, the number of new colorectal cancer cases in the United States decreased. This decline was largely driven by falling rates in adults aged 65 and older, who continue to have the highest overall rates of colorectal cancer. The drop in older adults may be due in part to increased colorectal cancer screening, which can detect and remove precancerous growths before they develop into cancer. However, trends vary by age group. Among adults younger than 50, the number of new cases of colorectal cancer rose by about 2.4% per year, the largest increase among all age groups. In people aged 50 to 64, the number of new cases increased slightly per year.

Since 1970, the death rate from colorectal cancer has declined in men and women. However, new cases and deaths from colorectal cancer remain higher among Black people than other racial groups. Studies show that Black people are not more likely than others to have precancerous growths.

Finding and treating colorectal cancer early may prevent death from colorectal cancer. Screening tests may be used to help find colorectal cancer.

Avoiding risk factors and increasing protective factors may help prevent cancer.

Avoiding cancer risk factors may help prevent certain cancers. Risk factors include smoking, having overweight, and not getting enough exercise. Increasing protective factors such as quitting smoking and exercising may also help prevent some cancers. Talk to your doctor or other health care professional about how you might lower your risk of cancer.

The following risk factors increase the risk of colorectal cancer:

The following protective factors decrease the risk of colorectal cancer:

Polyp removal

Most colorectal polyps are adenomas, which may develop into cancer. Removing colorectal polyps that are larger than 1 centimeter (pea-sized) may lower the risk of colorectal cancer. It is not known if removing smaller polyps lowers the risk of colorectal cancer.

The possible harms of polyp removal during colonoscopy or sigmoidoscopy include a tear in the wall of the colon and bleeding.

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It is not clear if the following affect the risk of colorectal cancer:

The following factors do not affect the risk of colorectal cancer:

Cancer prevention clinical trials are used to study ways to prevent cancer.

New ways to prevent colorectal cancer are being studied in clinical trials.

Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about colorectal cancer prevention. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Screening and Prevention Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Colorectal Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/colorectal/patient/colorectal-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389376]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Colorectal cancer is a disease in which malignant (cancer) cells form in the tissues of the colon or the rectum.

The colon and rectum are parts of the body’s digestive system. The digestive system removes and processes nutrients (vitamins, minerals, carbohydrates, fats, proteins, and water) from foods and helps pass waste material out of the body. The digestive system is made up of the mouth, throat, esophagus, stomach, and the small and large intestines. The colon (large bowel) is the first part of the large intestine and is about 5 feet long. Together, the rectum and anal canal make up the last part of the large intestine and are 6 to 8 inches long. The anal canal ends at the anus (the opening of the large intestine to the outside of the body).

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Cancer that begins in the colon is called colon cancer, and cancer that begins in the rectum is called rectal cancer. Cancer that begins in either of these organs may also be called colorectal cancer.

Other PDQ summaries containing information related to colorectal cancer include:

Colorectal cancer is the second leading cause of death from cancer in the United States.

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer death in the United States when numbers for men and women are combined. Between 2012 and 2021, the number of new colorectal cancer cases in the United States decreased. This decline was largely driven by falling rates in adults aged 65 and older, who continue to have the highest overall rates of colorectal cancer. The drop in older adults may be due in part to increased colorectal cancer screening, which can detect and remove precancerous growths before they develop into cancer. However, trends vary by age group. Among adults younger than 50, the number of new cases of colorectal cancer rose by about 2.4% per year, the largest increase among all age groups. In people aged 50 to 64, the number of new cases increased slightly per year.

Since 1970, the death rate from colorectal cancer has declined in men and women. However, new cases and deaths from colorectal cancer remain higher among Black people than other racial groups. Studies show that Black people are not more likely than others to have precancerous growths.

Different factors increase or decrease the risk of getting colorectal cancer.

Anything that increases your chance of getting a disease is called a risk factor. Anything that decreases your chance of getting a disease is called a protective factor.

Learn more about risk factors and protective factors for colorectal cancer in Colorectal Cancer Prevention.

Tests are used to screen for different types of cancer when a person does not have symptoms.

Scientists study screening tests to find those with the fewest harms and most benefits. Cancer screening trials also are meant to show whether early detection (finding cancer before it causes symptoms) helps a person live longer or decreases a person’s chance of dying from the disease. For some types of cancer, the chance of recovery is better if the disease is found and treated at an early stage.

Studies show that some screening tests for colorectal cancer help find cancer at an early stage and may decrease the number of deaths from the disease.

The following types of tests are used to screen for colorectal cancer:

Sigmoidoscopy

Sigmoidoscopy is a procedure to look inside the rectum and sigmoid (lower) colon for polyps, abnormal areas, or cancer. A sigmoidoscope is inserted through the rectum into the sigmoid colon. A sigmoidoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove polyps or tissue samples, which are checked under a microscope for signs of cancer.

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Colonoscopy

Colonoscopy is a procedure to look inside the rectum and colon for polyps, abnormal areas, or cancer. A colonoscope is inserted through the rectum into the colon. A colonoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove polyps or tissue samples, which are checked under a microscope for signs of cancer.

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Studies have shown that screening for colorectal cancer using digital rectal exam does not decrease the number of deaths from the disease.

A digital rectal exam (DRE) is an exam of the rectum that may be done as part of a routine physical exam. A doctor or nurse inserts a lubricated, gloved finger into the lower part of the rectum to feel for lumps or anything else that seems unusual. Study results have shown that DRE does not work as a screening method for colorectal cancer.

Screening tests for colorectal cancer are being studied in clinical trials.

Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Screening tests have risks.

Decisions about screening tests can be difficult. Not all screening tests are helpful and most have risks. Different screening tests have different risks or harms. Screening tests may cause anxiety when you are thinking about or getting ready for the test, or when there is a positive test result. Before having any screening test, you may want to discuss the test with your doctor. It is important to know the risks of the test, and whether it has been proven to reduce the risk of dying from cancer.

Talk to your doctor about your risk for colorectal cancer and the need for screening tests.

The following colorectal cancer screening tests have risks:

The results of an FOBT or DNA stool test may appear to be abnormal even though no cancer is found. A positive test result may lead to more testing, including colonoscopy.

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about colorectal cancer screening. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Screening and Prevention Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Colorectal Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/colorectal/patient/colorectal-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389230]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Evidence of Benefit Associated With Colorectal Cancer Screening

Based on solid evidence, screening for colorectal cancer (CRC) reduces CRC mortality. In addition, there is solid evidence that some CRC screening modalities also reduce CRC incidence. A meta-analysis of randomized controlled trials of flexible sigmoidoscopy found that screening with sigmoidoscopy reduces all-cause mortality.

Background

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide [1] and the second leading cause of cancer deaths in the United States.[2] It is estimated that in 2025 there will be 154,270 new cases diagnosed in the United States and 52,900 deaths due to this disease. From 2012 to 2021, incidence rates for CRC declined by about 1% per year overall due to screening uptake and changing patterns in risk factors. However, this declining incidence is confined to individuals aged 65 years and older. Between 2012 and 2021, incidence rates increased by 2.4% per year in individuals younger than 55 years and by 0.4% per year in individuals aged 50 to 64 years. Over the last decade, the mortality rate from CRC declined by 1.7% per year in both men and women.[2] Incidence is higher in men than in women. The incidence rates range from 34.5 per 100,000 per year in Asian or Pacific Islander men to 53.6 per 100,000 per year in American Indian or Alaska Native men. In women, the incidence rates range from 25.3 per 100,000 per year in Asian or Pacific Islander women to 45.5 per 100,000 per year in American Indian or Alaska Native women. The age-adjusted mortality rates are 15.4 per 100,000 per year in men and 10.8 per 100,000 per year in women. About 4.0% of Americans are expected to develop the disease within their lifetime, and the lifetime risk of dying from CRC is 1.4%.[3] Age-specific incidence and mortality rates show that most cases are diagnosed after age 54 years and 77% of cases occur in individuals aged 55 years and older; about 15% of CRC cases occur in individuals aged 45 to 54 years.[3–5]

An analysis of national data for 1975 to 2010 addressed long-term trends in CRC.[6] Incidence increased for men from 1975 to 1985, but there were marked declines from 1985 to 1995 for both men and women, followed by a nonsignificant increase from 1995 to 1998, then marked declines from 1998 to 2010. Death rates from CRC have declined since 1984 in both men and women, with an accelerated rate of decline since 2002 for men and since 2001 for women. From 1997 to 2010, CRC incidence declined for all racial and ethnic groups. The fastest annual rate of decline occurred in men and women aged 65 years or older. There was a trend of increasing short-term incidence rates for individuals younger than 50 years in most population subgroups. Incidence rates of distal colon and rectal cancers decreased in men and women for all ages combined. Incidence rates of proximal colon cancer also decreased in men and women for all races and ethnicities combined.

Risk Factors

Fecal Occult Blood Test (FOBT)

In FOBT testing, stool samples are collected and analyzed for the presence of small amounts of blood. The first generation of FOBTs used guaiac-based assays to detect blood, which are less sensitive and less specific than immunochemical-based testing. The now-classic randomized controlled trials (RCTs) that assessed colorectal cancer (CRC) mortality reduction all used guaiac-based testing. The finding of decreased CRC mortality provided a major foundation to draft CRC screening recommendations. The first-generation guaiac-based tests are being replaced with more sensitive and more specific immunochemical tests, which have not yet been assessed in RCTs with a no-screening control group.

In this setting, the RCT evidence about guaiac-based testing is reviewed briefly here, with further discussion of how immunochemical FOBT (iFOBT or FIT) may provide improved sensitivity and specificity. Generally, if guaiac FOBT (gFOBT) is acceptable as a screening test (as shown in RCTs), then a strong case can be made for using a more sensitive and more specific test like FIT.

gFOBT collection details vary somewhat for different tests, but they typically involve collection of as many as three different specimens on 3 different days, with small amounts from one specimen smeared by a wooden stick on a card with two windows or otherwise placed in a specimen container.

The guaiac test identifies peroxidase-like activity that is characteristic of human and nonhuman hemoglobin. Thus, the test records blood from ingested meat, upper airway bleeding such as epistaxis, upper gastrointestinal (GI) bleeding, and colonic lesions.

A systematic review regarding evidence of benefit was conducted through the Cochrane Collaboration. It examined all CRC screening randomized trials that involved gFOBT testing done on more than one occasion. The combined results showed that trial participants allocated to screening had a 16% lower CRC mortality (relative risk [RR], 0.84; 95% confidence interval [CI], 0.78–0.90). There was no difference in all-cause mortality between the screened groups and the control groups (RR, 1.00; 95% CI, 0.99–1.02). The trials reported a low positive predictive value (PPV) for the FOBT test, suggesting that most positive tests were false positives. The PPV was 5.0% to 18.7% in the trials using nonrehydrated slides (Funen and Nottingham studies), and it was 0.9% to 6.1% in the trials using rehydrated slides (Goteborg and Minnesota studies). The report contained no discussion about contamination in the control arms of the trials and no information about treatment by disease stage.[1,2]

On initial (prevalence) examinations, 1% to 5% of unselected individuals tested with gFOBT had positive test results. Of those who tested positive, approximately 2% to 10% had cancer and approximately 20% to 30% had adenomas,[3,4] depending on how the test was done. Data from RCTs of gFOBT testing are summarized in Table 2.

Four controlled clinical trials to evaluate the efficacy of screening with gFOBT have been completed or are in progress. While more sensitive stool blood tests based on measuring human hemoglobin have been developed (and are discussed later in this summary), results of their performance in RCTs have not yet been reported. For gFOBT, the Swedish trial was a targeted study for individuals aged 60 to 64 years.[5] The English trial selected candidates from lists of family practitioners.[6] The Danish trial offered screening to a population aged 45 to 75 years who were randomly assigned to a control or study group.[7,8]

The Minnesota trial randomly assigned 46,551 men and women aged 50 to 80 years to one of three arms: (1) CRC screening with gFOBT, (2) rehydrated (with some small percentage of unrehydrated) FOBT every year (n = 15,570) or (3) every 2 years (n = 15,587), or a control group (n = 15,394). This trial demonstrated that annual FOBT screening decreased mortality from CRC by 33% after 18 years of follow-up (RR, 0.67; 95% CI, 0.51–0.83, compared with the control group) and that biennial testing resulted in a 21% relative mortality reduction (RR, 0.79; 95% CI, 0.62–0.97).[9] Some part of the reduction may have been attributed to chance detection of cancer by colonoscopies; rehydration of guaiac test slides greatly increased positivity and consequently increased the number of colonoscopies performed.[10] Subsequent analyses by the Minnesota investigators using mathematical modeling suggested that for 75% to 84% of the patients, mortality reduction was achieved because of sensitive detection of CRCs by the test; chance detection played a modest role (16%–25% of the reduction).[11] Nearly 85% of patients with a positive test underwent diagnostic procedures that included colonoscopy or double-contrast barium enema plus flexible sigmoidoscopy (FS). After 18 years of follow-up, the incidence of CRC was reduced by 20% in the annually screened arm and 17% in the biennially screened arm. With follow-up through 30 years, there was a sustained reduction in CRC mortality of 32% in the annually screened arm (RR, 0.68; 95% CI, 0.56–0.82) and 22% in the biennially screened arm (RR, 0.78; 95% CI, 0.65–0.93). There was no reduction in all-cause mortality in either screened arm (RR, 1.00; 95% CI, 0.99–1.01 for the annually screened arm and RR, 0.99; 95% CI, 0.98–1.01 for the biennially screened arm).[12] Important information that was not reported includes the treatment of CRC cases by stage by arm and the extent of CRC screening in each arm by FOBT, sigmoidoscopy, or colonoscopy after the completion of the trial protocol.[12,13]

The English trial allocated approximately 76,000 individuals to each arm. Those in the screened arm were offered nonrehydrated gFOBT testing every 2 years for three to six rounds from 1985 to 1995. At a median follow-up of 7.8 years, 60% completed at least one test, and 38% completed all tests. Cumulative incidence of CRC was similar in both arms, and the trial reported an RR reduction of 15% in CRC mortality (odds ratio [OR], 0.85; 95% CI, 0.74–0.98).[14] The serious complication rate of colonoscopy was 0.5%. There were five deaths within 30 days of surgery for screen-detected CRC or adenoma in a total of 75,253 individuals screened.[15] After a median follow-up of 11.8 years, no difference in CRC incidence between the intervention and control groups was observed. The disease-specific mortality rate ratio associated with screening was 0.87 (0.78–0.97; P = .01). The rate ratio for death from all causes was 1.00 (0.98–1.02; P = .79).[16] When the median follow-up was extended to 19.5 years, there was a 9% reduction in CRC mortality (RR, 0.91; 95% CI, 0.84–0.98) but no reduction in CRC incidence (RR, 0.97; 95% CI, 0.91–1.03), or death from all causes (RR, 1.00; 95% CI, 0.99–1.02).[17]

The Danish trial in Funen, Denmark, entered approximately 31,000 individuals into two arms, in which individuals in the screened arm were offered nonrehydrated gFOBT testing every 2 years for nine rounds over a 17-year period. Sixty-seven percent of participants completed the first screen, and more than 90% of individuals invited to each subsequent screen underwent FOBT testing. This trial demonstrated an 18% reduction in CRC mortality at 10 years of follow-up,[18] 15% at 13 years of follow-up (RR, 0.85; 95% CI, 0.73–1.00),[19] and 11% at 17 years of follow-up (RR, 0.89; 95% CI, 0.78–1.01).[20] CRC incidence and overall mortality were virtually identical in both arms.

The Swedish trial in Goteborg enrolled all 68,308 citizens in the city who were born between 1918 and 1931 and were aged 60 to 64 years, and randomly assigned them to screening and control groups of nearly equal size. Participants in the control group were not contacted and were unaware they were part of the trial. Screening was offered at different frequencies to three different cohorts according to year of birth. Screening was done using the gFOBT Hemoccult-II test after dietary restriction. Nearly 92% of tests were rehydrated. Individuals with a positive test result were invited to an examination consisting of a case history, FS, and double-contrast barium enema. Follow-up ranged from 6 years 7 months to 19 years 5 months, depending on the date of enrollment. The primary end point was CRC-specific mortality. The overall screening compliance rate was 70%, and 47.2% of participants completed all screenings. Of the 2,180 participants with a positive test, 1,890 (86.7%) underwent a complete diagnostic evaluation with 104 cancers and 305 adenomas of at least 10 mm detected. In total, there were 721 CRCs (152 Dukes D, 184 Dukes C) in the screening group and 754 CRCs (161 Dukes D, 221 Dukes C) in the control group, with an incidence ratio of 0.96 (95% CI, 0.86–1.06). Deaths from CRC were 252 in the screening group and 300 in the control group, with a mortality ratio of 0.84 (95% CI, 0.71–0.99). This CRC mortality difference emerged after 9 years of follow-up. Deaths from all causes were very similar in the two groups, with a mortality ratio of 1.02 (95% CI, 0.99–1.06).[5]

Immunochemical FOBTs (iFOBT or FIT): Nonrandomized Controlled Trial Evidence to Assess Lesion Detection

The immunochemical FOBT (iFOBT or FIT) was developed to detect intact human hemoglobin. The advantage of FIT over gFOBT is that it does not detect hemoglobin from nonhuman dietary sources. Also, FIT does not detect partly digested human hemoglobin that comes from the upper respiratory or GI tract. Preliminary studies of several commercially developed FIT tests define their sensitivity and specificity compared with concurrently performed colonoscopy. The studies also examine these outcomes for different cutpoints, and the benefit of multiple versus single stool samples.[25,26]

Overall, FIT testing is much more sensitive than gFOBT, and it is more sensitive for cancers than for benign neoplasias. As expected, higher cutpoints decrease sensitivity and increase specificity. Fecal immunochemical tests may vary with regard to numbers of stools tested and cutoff values for a positive result.[26]

A systematic review of FIT studies in 2019 found 31 studies, with 120,255 participants and 18 types of FIT tests, that used screening colonoscopy as the reference standard, thus allowing calculation of test sensitivity and specificity.[27] Performance depended on the threshold for a positive result, so that a threshold of 10 µg/g (micrograms of hemoglobin per gram of feces) resulted in a CRC sensitivity of 0.91 (95% CI, 0.84–0.95) and a specificity of 0.90 (95% CI, 0.86–0.93), while a threshold greater than 20 µg/g resulted in a sensitivity of 0.71 (95% CI, 0.56–0.83) with specificity of 0.95 (95% CI, 0.94–0.96). For advanced adenomas, at a threshold of 10 µg/g, sensitivity was 0.40 (95% CI, 0.33–0.47) with a specificity of 0.90 (95% CI, 0.87–0.93). Comparison of three FITs at three thresholds was inconclusive because CIs overlapped, and the comparisons were across rather than within studies. Overall, FIT appears to provide a substantially improved sensitivity compared with gFOBT, although with some compromise in specificity.

The diagnostic sensitivity of FIT testing may vary depending on lesion location in the colon. Proximal lesions may be harder to detect for several reasons, including that they may arise from serrated lesions that are flat and, because they are less vascular than traditional adenomas, tend to bleed less frequently. In a population-based screening program of every-other-year FIT (set to detect 100 ng of hemoglobin per mL of buffer) testing, individuals who had six FITs over time were assessed to learn the frequency with which proximal and distal lesions were discovered.[28] Over 12 years (2002–2014), 123,000 participants had 441,000 FITs. The detection rate for proximal colon cancer declined only from the first to the second screening round (0.63–0.36 per 1,000 screened participants), while the rate for both distal colon and rectal cancer decreased across all six rounds (distal cancer, 1.65 in the first round to 0.17 in the sixth round). (Similar trends occurred for advanced adenomas.) The proportional interval cancer rate—the number of cancers observed versus expected—was higher in the proximal colon than in the distal colon (25.2% vs. 6.0%), suggesting that many proximal cancers (or their immediate precursors) may have been missed by FIT. These results suggest that FIT is less sensitive for proximal CRC and certainly for advanced adenomas, although it is possible that the miss rate may have been inflated if colonoscopy done in response to a positive FIT had missed a precursor lesion. Overall, these results raise questions about the degree of efficacy of FIT in preventing proximal CRC mortality.

The performance and acceptability of FIT over time was assessed by Kaiser-Permanente of Northern and Southern California in a screening program. A retrospective cohort of 323,349 persons aged 50 to 70 years was followed for up to four screening rounds over 4 years. Of patients invited, participation in round one was 48.2%, and of those remaining eligible, 75.3% to 86.1% participated in subsequent rounds. The authors reported that “programmatic FIT screening detected 80.4% of patients with CRC diagnosed within 1 year of testing, including 84.5% in round one and 73.4% to 78.0% in subsequent rounds.” An important observation was the degree of participation found. One limitation of the study is that it was not clear how work-up bias was addressed; e.g., when individuals with a positive test result are preferentially worked up to ascertain the presence or absence of CRC, while individuals with a negative test, but who might have CRC, are not. Although a look-back method was used to ascertain whether an individual had cancer, it is not clear that the duration of follow-up was long enough to discover everyone who should have been included in the denominator of the sensitivity calculation. Nevertheless, the results suggested that subsequent FIT results were at least partially independent of previous results. Longer follow-up may help clarify this issue. Mortality reduction could not be assessed in this study.[29]

Potential false-positive test results because of an increased risk of upper GI bleeding are of concern with FOBT testing and pretest protocols, therefore; low-dose aspirin regimens are discontinued for a week or more before FOBT. The performance of FIT was tested in an ongoing diagnostic study (2005–2009) at 20 internal medicine GI practices in southern Germany. Nineteen hundred seventy-nine patients (233 regular low-dose aspirin users and 1,746 never users) were identified in the records for inclusion in the analysis. All patients provided one stool sample taken within a week before colonoscopy preparation, which was collected according to instructions in a container that was kept refrigerated or frozen until rendered to the clinic on the day of colonoscopy, and the patients agreed to complete a standard questionnaire regarding the use of analgesics and low-dose aspirin (for prevention of cardiovascular disease). Stool samples were thawed within a median of 4 days after arrival at the central laboratory (shipped frozen from the recipient clinics). Fecal occult blood levels were measured by two automated FIT tests according to the manufacturer’s instructions (RIDASCREEN Haemoglobin and RIDASCREEN Haemo-/Haptoglobin Complex, r-biopharm, Bensheim, Germany) following clinical procedures and blinded to colonoscopy results. Advanced neoplasms were found in 24 aspirin users (10.3%) and in 181 nonusers (10.4%). At the cut point recommended by the manufacturer, sensitivities for the two tests were as follows: 70.8% (95% CI, 48.9%–87.4%) for users compared with 35.9% (95% CI, 28.9%–43.4%) for nonusers for the Haemoglobin test (P = .001) and 58.3% (95% CI, 36.6%–77.9%) for users compared with 32% (95% CI, 25.3%–39.4%) for nonusers for the Haemo-/Haptoglobin test (P = .01). Specificities were as follows: 85.7% (95% CI, 80.2%–90.1%) for users compared with 89.2% (95% CI, 87.6%–90.7%) for nonusers for the Haemoglobin test (P = .13) and 85.7% (95% CI, 80.2%–90.1%) for users compared with 91.1% (95% CI, 89.5%–92.4%) for nonusers for the Haemo-/Haptoglobin test (P = .01). For these FITs, sensitivity for advanced neoplasms was notably higher with the use of low-dose aspirin while specificity was only slightly reduced, suggesting that there might be an advantage of aspirin use to increase sensitivity without much decrease in specificity.[30]

Sigmoidoscopy

The flexible fiberoptic sigmoidoscope was introduced in 1969. The 60 cm flexible sigmoidoscope became available in 1976.[31] The flexible sigmoidoscope permits a more complete examination of the distal colon with more acceptable patient tolerance than the older rigid sigmoidoscope. The rigid instrument can discover 25% of polyps, while the 60-cm scope can find as many as 65% of them. The finding of an adenoma by FS may warrant a colonoscopy to evaluate the more proximal portion of the colon.[32,33] The prevalence of advanced proximal neoplasia is increased in patients with a villous or tubulovillous adenoma distally and is also increased in those aged 65 years or older with a positive family history of CRC and with multiple distal adenomas.[34] Most of these adenomas are polypoid, flat, and depressed lesions, which may be somewhat more prevalent than previously recognized.[35]

Four major sigmoidoscopy screening RCTs have reported incidence and mortality results (a fifth, the Telemark trial in Norway, was very small, with 800 total participants). These are the Norwegian Colorectal Cancer Prevention (NORCCAP) trial; the United Kingdom Flexible Sigmoidoscopy Screening Trial (UKFSST); the Screening for COlon REctum (SCORE) trial in Italy; and the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (see Table 3). Participants were aged 55 to 74 years in PLCO and aged 55 to 64 years in the other three trials. Together, the trials enrolled 166,000 participants in the screened groups and 250,000 participants in the control groups. Median follow-up was approximately 11 years for each group. Results were summarized in three systematic reviews. There was an 18% relative reduction in CRC incidence (RR, 0.82; 95% CI, 0.75–0.89), an overall 28% relative reduction in CRC mortality (RR, 0.72; 95% CI, 0.65–0.80), a 31% relative reduction in the incidence of distal CRC (RR, 0.69; 95% CI, 0.63–0.74), and a 46% relative reduction in the mortality of distal CRC (RR, 0.54; 95% CI, 0.43–0.67).[36] A meta-analysis showed a statistically significant, although clinically small, effect on all-cause mortality (RR, 0.97; 95% CI, 0.96–0.99).[37]

Three of the four trials above published long-term follow-up analyses of trial results. For UKFSST, median follow-up was 17.1 years. The RRs for CRC incidence and mortality were similar to those originally reported: an RR of 0.70 (95% CI, 0.62–0.79) for CRC mortality and an RR of 0.74 (95% CI, 0.70–0.80) for CRC incidence. For the PLCO trial, median follow-up was 15.8 years for incidence and 16.8 years for mortality; RRs were 0.75 (95% CI, 0.66–0.85) for CRC mortality and 0.82 (95% CI, 0.76–0.88) for CRC incidence. Median follow-up in the NORCCAP trial was approximately 15 years; HRs were 0.79 (95% CI, 0.65–0.96) for CRC mortality and 0.78 (95% CI, 0.70–0.87) for CRC incidence.[38,39] A pooled analysis of the four trials, using data through 15 years of follow-up and restricted to those aged 55 to 64 years at randomization, showed a rate ratio of 0.79 (95% CI, 0.75–0.83) for CRC incidence and 0.80 (95% CI, 0.72–0.88) for CRC mortality.[40]

There are no strong direct data from studies of sigmoidoscopy to determine the optimal frequency of screening tests in programs of screening.

Combination of FOBT and Flexible Sigmoidoscopy: Impact on Neoplasm Detection

A combination of FOBT and sigmoidoscopy might increase the detection of lesions in the left colon (compared with sigmoidoscopy alone) while also increasing the detection of lesions in the right colon. Sigmoidoscopy detects lesions in the left colon directly but detects lesions in the right colon only indirectly when a positive sigmoidoscopy (that may variously be defined as a finding of advanced adenoma, any adenoma, or any polyp) is used to trigger a colonoscopic examination of the whole colon.

In 2,885 veterans (97% male; mean age, 63 years), the prevalence of advanced adenoma at colonoscopy was 10.6%. It was estimated that combined screening with one-time FOBT and sigmoidoscopy would detect 75.8% (95% CI, 71.0%–80.6%) of advanced neoplasms. Examination of the rectum and sigmoid colon during colonoscopy was defined as a surrogate for sigmoidoscopy. This represented a small but statistically insignificant increase in the rate of detection of advanced neoplasia when compared with FS alone (70.3%; 95% CI, 65.2%–75.4%). The latter result could be achieved assuming that all patients with an adenoma in the distal colon undergo complete colonoscopy. Advanced neoplasia was defined as a lesion measuring at least 10 mm in diameter, containing 25% or more villous histology, high-grade dysplasia, or invasive cancer.[41] One-time use of FOBT differs from the annual or biennial application reported in those studies summarized in Table 2.

A study of 21,794 asymptomatic individuals (72% were men) who had both colonoscopy and FIT for occult blood compared the detection of proximal cancers as triggered by different test results. FIT alone resulted in a sensitivity of 58.3% and a specificity of 94.5% for proximal cancer diagnosis. FIT plus the finding of advanced neoplasia in the rectosigmoid colon yielded a sensitivity of 62.5% and a specificity of 93%. In this study, the addition of sigmoidoscopy to FIT did not substantially improve the detection of proximal colon cancers, compared with FIT alone.[42]

Colonoscopy

Virtual Colonoscopy (Computed Tomographic Colonography [CTC])

Virtual colonoscopy (also known as CTC or CT pneumocolon) refers to the examination of computer-generated images of the colon constructed from data obtained from an abdominal CT scan. These images simulate the effect of a conventional colonoscopy. Patients must take laxatives to clean the colon before the procedure, and the colon is insufflated with air (sometimes carbon dioxide) by insertion of a rectal tube just before radiographic examination.[57]

The American College of Radiology Imaging Network group conducted a large, paired-design study, with 2,531 participants at average risk (prevalence of polyps or cancer ≥10 mm, 4%; mean age, about 58 years) screened with both CTC and optical colonoscopy (OC). The gold standard was the OC, including repeat OC exams for people with lesions found by CTC but not by OC. Of 109 people with at least one adenoma or cancer 10 mm or larger, 98 (90%) were detected by CTC (referring everyone with a CTC lesion of ≥5 mm). Specificity was 86%, and PPV was 23%. This study raises several concerns, including the following:

Unknowns from the study include the following for either OC or CTC:[58]

Another study reported similar sensitivity and specificity in individuals with an increased risk of CRC.[59] In this study, the sensitivity of OC could not be determined because it was done in an unblinded manner. This cross-sectional study suggested that virtual colonoscopy might be an acceptable screening or surveillance test for individuals at high risk of CRC, but it did not address outcome or frequency of testing in those at high risk.

Some studies have assessed how well virtual colonoscopy can detect colorectal polyps without a laxative prep. The question is of great importance for implementation because the laxative prep required by both conventional colonoscopy and virtual colonoscopy is considered a great disadvantage by patients. By tagging feces with iodinated contrast material ingested for several days before the procedure, investigators in one study were able to detect lesions larger than 8 mm with 95% sensitivity and 92% specificity.[60] The particular tagging material used in this study caused about 10% of patients to become nauseated; however, other materials are being assessed.

Another study [61] used a low-fiber diet, orally ingested contrast, and “electronic cleansing,” a process that subtracts tagged feces. CTC identified 91% of adenomas 10 mm or larger, but it detected fewer (70%) lesions of at least 8 mm. Patients who received both CTC and OC preferred CTC to OC (290 vs. 175). This study shows that CTC without a laxative prep detects small 1-cm lesions with high sensitivity and is acceptable to patients. Long-term utilization of CTC will depend on several issues, including the frequency of follow-up exams that would be needed to detect smaller lesions that were undetected and may grow over time.

Extracolonic abnormalities are commonly detected with CTC. Fifteen percent of patients in an Australian series of 100 patients, referred for colonography because of symptoms or family history, were found to have extracolonic findings, and 11% of the patients needed further medical workups for renal, splenic, uterine, liver, and gallbladder abnormalities.[62] In another study, 59% of 111 symptomatic patients referred for clinical colonoscopy in a Swedish hospital between June 1998 and September 1999 were found to have moderate or major extracolonic conditions on CTC. CTC was performed immediately before a colonoscopy, and these findings required further evaluation. The extent to which follow-up of these incidental findings benefited patients is unknown.[63]

Sixty-nine percent of 681 asymptomatic patients in Minnesota had extracolonic findings, 10% of which were deemed highly important by the investigators; these patients required further medical workup. Suspected abnormalities involved kidney (34), chest (22), liver (8), ovary (6), renal or splenic arteries (4), retroperitoneum (3), and pancreas (1);[64] however, the extent to which these findings contribute to benefits or harms is uncertain. Two other studies, one large (N = 2,195) and one small (n = 136) examined the moderate or high importance of extracolonic findings from CTC. The larger study [65] found that 8.6% of patients had an extracolonic finding of at least moderate importance, while 24% of patients in the smaller study [66] required some evaluation for an extracolonic finding. The larger study found nine cancers from these evaluations, at a partial cost (they did not include all costs) of $98.56 per patient initially screened. The smaller study found no important lesions from evaluation, at a cost of $248 per person screened. Both of these estimates of cost are higher than previous studies have found. The extent to which any patients benefited from the detection of extracolonic findings is not clear. Because both studies were conducted in academic medical centers, the generalizability to other settings is also not clear. Neither of these studies examined the effect of extracolonic findings on patient anxiety and psychological function.

Technical improvements involving both the interpretation methodology, such as three-dimensional (3-D) imaging, and bowel preparation are under study in many centers. While specificity for detection of polyps is homogeneously high in many studies, sensitivity can vary widely. These variations are attributable to a number of factors including characteristics of the CT scanner and detector, width of collimation, mode of imaging (two dimensional [2-D] vs. 3-D and/or fly-through), and variability in the expertise of radiologists.[67]

Digital Rectal Examination

A case-control study reported that routine digital rectal examination was not associated with any statistically significant reduction in mortality from distal rectal cancer.[68]

Detection of DNA Mutations in the Stool

The molecular genetic changes that are associated with the development of colorectal adenomas and carcinoma have been well characterized.[69] Advanced techniques have been developed to detect several of these gene mutations that shed into the stool.[70–73] Stool DNA testing was recently assessed in a prospective study of asymptomatic individuals who received colonoscopy, three-card FOBT (Hemoccult II), and stool DNA testing based on a panel of markers assessing 21 mutations. Conducted in a blinded way with prestated hypotheses and analyses, the study found that among 4,404 patients, the DNA panel had a sensitivity for CRC of 51.6% (for all stages of CRC) versus 12.9% for Hemoccult II, while the false-positive rates were 5.6% and 4.8%, respectively.[74,75]

A next-generation multitargeted stool test combined methylation markers for NDRG4 and BMP3, several KRAS mutations, and a human hemoglobin immunoassay. The markers, each quantitated separately, were combined using an algorithm in a prespecified multivariable analysis. In the DeeP-C trial, the assay’s sensitivity and specificity were compared with a commercial FIT test (OC FIT-CHEK Polymedco), using colonoscopy as the gold standard. Among 12,776 participants aged 50 to 84 years (weighted toward >65 years) who underwent colonoscopy screening and were enrolled at 90 sites across the United States and Canada between 2011 and 2012, 9,989 had fully evaluable results. There were 65 CRC and 757 advanced adenomas or sessile serrated polyps 1 cm or greater. The sensitivity for CRC was 92.3% (60 of 65 CRC) for the multitargeted test and 73.8% for FIT. Sensitivity for advanced lesions was 42.4% for the multitargeted test and 23.8% for FIT. Sensitivity for high-grade dysplasia was 69.2% for the multitarget test and 46.2% for FIT. Sensitivity for serrated sessile polyps 1 cm or greater was 42.4% for the multitargeted test and 5.1% for FIT. Specificities were 86.6% for the multitargeted test and 94.9% for FIT, using nonadvanced or negative colonoscopy results, and were 89.8% and 96.4% for totally negative colonoscopy results. A receiver operating characteristic (ROC) analysis showed that the multitargeted test has higher sensitivity than FIT alone, even when the FIT cutoff is reduced to try to increase sensitivity. A limitation is that there were no data about performance of repeated testing over time and what may be an appropriate testing interval.[76]

A newer version of the multitargeted stool DNA (mt-sDNA) test was recently developed. This test incorporates a novel molecular marker panel that includes methylated DNA markers of four genes—LASS4, LRRC4, PPP2R5C, and ZDHHC1—while retaining the fecal hemoglobin marker. In the BLUE-C trial, which was structured similarly to the DeeP-C trial, the investigators compared the sensitivity and specificity of the newer version of the mt-sDNA test with FIT (OC FIT-CHEK Polymedco), using colonoscopy as the gold standard for detecting stage I, II, and III CRC and advanced precancerous lesions in average-risk individuals older than 40 years.[77]

Overall, the multitargeted test was more sensitive than FIT for both CRC and advanced precancerous lesions, but the test was less specific.[76,77]

Cell-Free DNA (cfDNA) Blood Test

A cfDNA blood test was developed for the detection of CRC. This test analyzes plasma cfDNA to identify aberrant DNA-methylation status, abnormal DNA-fragmentation patterns, and the presence or absence of somatic pathogenic variants in the APC and KRAS genes. In the ECLIPSE trial, researchers conducted a prospective multicenter study at 265 primary care sites and endoscopy centers across the United States.[78] The trial aimed to evaluate the performance of the cfDNA blood-based test in detecting asymptomatic and early-stage CRC in a screening-relevant population.

Overall, the study team demonstrated the feasibility of using plasma cfDNA to screen for CRC. However, the relatively low sensitivity for detecting advanced precancerous lesions presents a limitation. Currently, the cfDNA blood-based test is still awaiting approval by the U.S. Food and Drug Administration and is not covered by Medicare.[78]

Adherence to Screening

Benefit from CRC screening can only occur if eligible people are screened. There have been problems with screening adherence, particularly for low-income and uninsured people. There are also concerns that some people may be less likely to adhere to screening with a colonoscopy than with fecal tests. One well-conducted RCT found that, among an uninsured population, mailed FIT-kit outreach and follow-up reminder phone calls resulted in an adherence rate of 40.7%. Mailed colonoscopy invitations and follow-up phone reminders resulted in a 24.6% adherence rate. The usual-care adherence rate in this trial was 12.1%.[79]

Tailoring Screening to Risk

Benefit of screening might be improved by tailoring the recommended screening test to a person’s degree of CRC risk. For example, if a subgroup of young women were to have a substantially lower risk of proximal neoplasms, then recommending sigmoidoscopy instead of colonoscopy might lead to higher compliance (the U.S. Preventive Services Task Force recommends both procedures without preference, as part of a program of screening those at average risk).

In a study to identify an average-risk group who had a higher versus lower risk of advanced neoplasia (CRC and advanced adenomas) anywhere in the colon, 2,993 individuals having a screening colonoscopy were stratified by age, sex, waist circumference, smoking, and family history (those in high-risk family categories, e.g., Lynch syndrome or adenomatous polyposis coli, were excluded). In a classification system derived in a training set, the risks of advanced neoplasm in four groups were: 1.92%, 4.88%, 9.93%, and 24%. In the two lowest-risk groups, sigmoidoscopy would have detected 51 (73%) of 70 advanced neoplasms. In the independent validation set, results were similar. Whether this system increases overall compliance has yet to be determined.[80]

A similar stratification system based on age, sex, smoking, and family history—and combined with FIT—was tested in Asia to determine whether use of the stratification system plus FIT could detect which people needed colonoscopy. If either the stratification system or FIT was positive, a person was recommended for colonoscopy. Using this strategy, 95% of those with CRC were correctly told to have colonoscopy.[81]

Overview

The tables for each screening test below show the magnitude of burden for several categories of harms encountered along the screening cascade. The magnitude of harms is a combination of the frequency and severity of harm, as perceived by the patient.

Harms are defined broadly as any negative effect on individuals or populations resulting from being involved in the screening process (cascade) compared with not screening. Potential harms are organized according to the type of harm (e.g., physical, psychological, and hassle/opportunity costs) and when they occur in the screening cascade (e.g., screening test/workup; screening test/workup results; surveillance and surveillance results; and early treatment and overtreatment). For example, potential harms of screening colonoscopy include harms of the screening test itself (e.g., perforation and bleeding), results of the screening test (e.g., anxiety from an abnormal result), surveillance (e.g., harms of more frequent colonoscopies), and treatment (e.g., earlier treatment or overtreatment). Harms are also associated with the workup for other colorectal cancer screening tests (e.g., colonoscopy for positive fecal occult blood test [FOBT]). A recent study of three major hospitals found that 71% of endoscopes tested positive for bacteria after cleaning and high-level disinfection of the scopes. This raises concern for endoscopy-associated pathogen transmission and patient safety, although no patients were involved in the study and the implications for patients are unknown.[1] For all aspects of participating in the screening cascade, there are time/effort and opportunity costs (nonfinancial harms) for the patient. The following tables do not include any financial harms to the patient/family, nor any psychological harm from anticipation of future financial costs related to screening.

Evidence Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about colorectal cancer screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Colorectal Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/colorectal/hp/colorectal-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389266]

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Kidney cancer is a disease in which malignant (cancer) cells form in tubules of the kidney.

Kidney cancer (also called renal cell cancer) is cancer that starts in the lining of very small tubes in the kidney called renal tubules. There are two kidneys, one on each side of the backbone, above the waist. Tubules in the kidneys filter and clean the blood. They take out waste products and make urine. The urine passes from each kidney through a long tube called a ureter into the bladder. The bladder holds the urine until it passes through the urethra and leaves the body.

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Cancer that starts in the ureters or the renal pelvis (the part of the kidney that collects urine and drains it to the ureters) is called urothelial cancer. This kind of cancer is different from renal cell cancer and is not associated with the hereditary cancer syndromes described in this summary. Urothelial cancer of the renal pelvis may be associated with another hereditary condition called Lynch syndrome. To learn more, see the health professional summary on Genetics of Colorectal Cancer.

Having certain hereditary syndromes can increase the risk of kidney cancer.

Most of the time, kidney cancer risk is not passed down from parent to child. Kidney cancer that affects multiple generations of a family is called hereditary kidney cancer. Hereditary kidney cancer accounts for only 5%‒8% of all kidney cancers. It is usually linked to a hereditary cancer syndrome. A hereditary cancer syndrome is a disorder in which family members have a higher-than-average risk of developing a certain type or types of cancer. Hereditary cancer syndromes are caused by inherited, harmful genetic changes (also called pathogenic variants or mutations) in certain genes. Hereditary cancer syndromes are sometimes called inherited cancer syndromes or family cancer syndromes. People with the hereditary cancer syndromes described in this summary have an increased risk of kidney cancer.

The hereditary cancer syndromes described in this summary are:

Every person inherits two copies of each gene, one from each parent. These syndromes occur when a person inherits a mutation in one copy of the gene associated with the syndrome. This form of inheritance is called autosomal dominant inheritance.

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Hereditary and non-inherited kidney cancers are different in several ways.

This page provides information about hereditary syndromes associated with kidney cancer. It does not cover information about sporadic kidney cancer or somatic mutations found during tumor sequencing.

Genetic counseling is a communication process between a specially trained health professional and a person concerned about the genetic risk of disease.

It is not always easy to determine whether a condition in a family is inherited. Genetic counselors and other specially trained health professionals can help patients understand their personal and family medical history, their options for genetic testing, and the risks and benefits of learning genetic information. If a patient chooses to get genetic testing, it may be done using a sample of blood, saliva, or skin. Genetic test results can reveal information about other family members and can create tension in the family. Genetic counselors can help people cope with their genetic testing results, including how to discuss the results with family members.

Whether a person should get tested for hereditary kidney cancer depends on certain factors.

Certain clues in the medical history or family history may lead health professionals to think that a person may have a hereditary syndrome. With kidney cancer, people who have one or more of the following criteria may be referred for genetic counseling and testing:

Four hereditary kidney cancer syndromes and the genes that cause them have been identified.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

HLRCC was considered rare, but it may be one of the most common hereditary cancer syndromes. Some people who have HLRCC may not have symptoms. HLRCC is caused by harmful changes (also called mutations or pathogenic variants) in the FH gene. People with HLRCC could have an increased risk of kidney cancer. The risk may be higher in males with FH mutations. Black people diagnosed with kidney cancer have more FH mutations than people from other racial and ethnic groups. HLRCC is associated with a unique type of kidney cancer that can be fast growing. People with HLRCC may also develop leiomyomas (benign smooth-muscle tumors) in the skin and uterus (fibroids) or paragangliomas (benign tumors near adrenal glands, blood vessels, or nerves).

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The FH gene makes a protein called fumarase. Fumarase helps cells use oxygen and produce energy. When the FH gene is mutated, cells are not able to use oxygen, which may lead to cancer. HLRCC is inherited in an autosomal dominant manner. This means that if one parent has HLRCC, there is a 50% (1 in 2) chance their child will inherit the mutation in the FH gene.

Learn more about HLRCC from the NCATS Genetic and Rare Diseases Information Center.

Von Hippel-Lindau Disease (VHL)

VHL is a rare hereditary syndrome that is caused by harmful changes (also called mutations or pathogenic variants) in the VHL gene. People with VHL have an increased risk of kidney cancer and renal cysts. VHL is associated with a clear-cell type kidney cancer, which is typically slow growing. People with VHL may also develop malignant (cancer) and benign (noncancer) tumors in many parts of the body, including the central nervous system, retina, pancreas, adrenal glands, endolymphatic sac, epididymis (in males), and broad ligament (in females).

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The VHL gene is a type of gene called tumor suppressor gene. Normally, the VHL gene prevents cells from growing and dividing too quickly. When the VHL gene is mutated in certain ways and loses its protective function, uncontrolled cell growth may lead to cancer. VHL is inherited in an autosomal dominant manner. If one parent has VHL, there is a 50% (1 in 2) chance their child will inherit the harmful genetic change in the VHL gene.

Learn more about VHL from the NCATS Genetic and Rare Diseases Information Center.

Birt-Hogg-Dubé Syndrome (BHD)

BHD is a rare hereditary syndrome caused by harmful changes (also called mutations or pathogenic variants) in the FLCN gene. People with BHD have an increased risk of multiple types of kidney cancer that are typically slow growing. People with BHD may also develop skin tumors called fibrofolliculomas, lung cysts, and spontaneous pneumothorax (collapsed lung).

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The FLCN gene is a tumor suppressor gene. Normally, the FLCN gene prevents cells from growing and dividing too quickly. When the FLCN gene is mutated, uncontrolled cell growth may lead to cancer. BHD is inherited in an autosomal dominant manner. This means that if one parent has BHD, there is a 50% (1 in 2) chance their child will inherit the mutation in the FLCN gene.

Learn more about BHD from the NCATS Genetic and Rare Diseases Information Center.

Hereditary Papillary Renal Cancer (HPRC)

HPRC is a rare hereditary syndrome caused by harmful changes (also called mutations or pathogenic variants) in the MET gene. People with HPRC have an increased risk of a type of kidney cancer called papillary kidney cancer, which is typically slow growing. Papillary kidney cancer forms in the cells lining the very small tubes in the kidney called renal tubules.

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The MET gene makes a protein called MET that is involved in cell signaling and growth. When the MET gene is mutated, cells may not respond to signals that normally prevent them from growing, causing cancer to develop. HPRC is inherited in an autosomal dominant manner. This means that if one parent has HPRC, there is a 50% (1 in 2) chance their child will inherit the mutation in the MET gene.

Learn more about papillary kidney cancer from the NCATS Genetic and Rare Diseases Information Center.

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

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Purpose of This Summary

This PDQ cancer information summary has current information about the genetics of kidney cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

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Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Cancer Genetics Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

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PDQ® Cancer Genetics Editorial Board. PDQ Hereditary Kidney Cancer Syndromes. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/kidney/patient/kidney-genetics-pdq. Accessed <MM/DD/YYYY>.

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Colorectal Polyps as Precursors to Colorectal Cancer (CRC)

Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer, and are predominantly epithelial-derived tumors (i.e., adenomas or adenocarcinomas).

Transformation of any polyp into cancer goes through the adenoma-carcinoma sequence. Polyps that have traditionally been considered nonneoplastic include those of the hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid types. However, in certain circumstances, hamartomatous and juvenile polyps can progress into cancer.

Research, however, does suggest a substantial risk of colon cancer in individuals with juvenile polyposis syndrome and Peutz-Jeghers syndrome, although the nonadenomatous polyps associated with these syndromes have historically been viewed as nonneoplastic.[5–7]

Epidemiological studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.[8]

Two complementary interpretations of this observation are as follows:

More than 95% of CRCs are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into three histological types, with increasing malignant potential: tubular, tubulovillous, and villous. Adenocarcinomas are generally considered to arise from adenomas,[9–13] based upon the following important observations:

The following three characteristics of adenomas are highly correlated with the potential to transform into cancer:[14]

In addition, removal of adenomatous polyps is associated with reduced CRC incidence.[16,17] While most adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large, flat, and depressed lesions may be more likely to be severely dysplastic, although this remains to be clearly proven.[18,19] Specialized techniques may be needed to identify, biopsy, and remove such lesions.[20]

Family History as a Risk Factor for CRC

Some of the earliest studies of family history of CRC were those of Utah families that reported a higher percentage of deaths from CRC (3.9%) among the first-degree relatives (FDRs) of patients who had died from CRC than among sex-matched and age-matched controls (1.2%).[21] This difference has since been replicated in numerous studies that have consistently found that FDRs of affected cases are themselves at a twofold to threefold increased risk of CRC. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.[22–27]

A systematic review and meta-analysis of familial CRC risk has been reported.[28] Of 24 studies included in the analysis, all but one reported an increased risk of CRC if there was an affected FDR. The relative risk (RR) for CRC in the pooled study was 2.25 (95% confidence interval [CI], 2.00–2.53) if there was an affected FDR. In 8 of 11 studies, if the index cancer arose in the colon, the risk was slightly higher than if it arose in the rectum. The pooled analysis revealed an RR in relatives of colon and rectal cancer patients of 2.42 (95% CI, 2.20–2.65) and 1.89 (95% CI, 1.62–2.21), respectively. The analysis did not reveal a difference in RR for colon cancer based on location of the tumor (right side vs. left side).

The number of affected family members and age at cancer diagnosis correlated with the CRC risk. In studies reporting more than one FDR with CRC, the RR was 3.76 (95% CI, 2.56–5.51). The highest RR was observed when the index case was diagnosed in individuals younger than 45 years (RR, 3.87; 95% CI, 2.40–6.22) compared with family members of index cases diagnosed at ages 45 to 59 years (RR, 2.25; 95% CI, 1.85–2.72), and to family members of index cases diagnosed at age 60 years or older (RR, 1.82; 95% CI, 1.47–2.25). In this meta-analysis, the familial risk of CRC associated with adenoma in an FDR was analyzed. The pooled analysis demonstrated an RR for CRC of 1.99 (95% CI, 1.55–2.55) in individuals who had an FDR with an adenoma.[28] This finding has been corroborated.[29] Other studies have reported that age at diagnosis of the adenoma influences the CRC risk, with younger age at adenoma diagnosis associated with higher RR.[30,31] As with any meta-analysis, there could be potential biases that might affect the results of the analysis, including incomplete and nonrandom ascertainment of studies included; publication bias; and heterogeneity between studies relative to design, target populations, and control selection. This study is reinforcement that there are significant associations between familial CRC risk, age at diagnosis of both CRC and adenomas, and multiplicity of affected family members.

When the family history includes two or more relatives with CRC, the possibility of a genetic syndrome is increased substantially. The first step in this evaluation is a detailed review of the family history to determine the number of relatives affected, their relationship to each other, the age at which the CRC was diagnosed, the presence of multiple primary CRCs, and the presence of any other cancers (e.g., endometrial) consistent with an inherited CRC syndrome. (Refer to the Major Genetic Syndromes section of this summary for more information.) Computer models are now available to estimate the probability of developing CRC.[32] These models can be helpful in providing genetic counseling to individuals at average risk and high risk of developing cancer. In addition, at least three validated models are also available for predicting the probability of carrying a pathogenic variant in a mismatch repair (MMR) gene.[33–35]

Figure 1 shows the proportion of CRC cases that arise in various family risk settings.[36]

Enlarge

Inheritance of CRC Predisposition

Several genes associated with CRC risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. Almost all pathogenic variants known to cause a predisposition to CRC are inherited in an autosomal dominant fashion.[37] One example of autosomal recessive inheritance, MUTYH-associated polyposis (MAP), has been identified. (Refer to the MUTYH-Associated Polyposis [MAP] section of this summary for more information.) Thus, the family characteristics that suggest autosomal dominant inheritance of cancer predisposition are important indicators of high risk and of the possible presence of a cancer-predisposing pathogenic variant. These include the following:

The two most common causes of hereditary CRC are FAP (including AFAP), due to germline pathogenic variants in the APC gene,[39–46] and Lynch syndrome (previously called hereditary nonpolyposis colorectal cancer [HNPCC]), which is caused by germline pathogenic variants in DNA MMR genes.[47–50] (Figure 2 depicts a classic family with Lynch syndrome, highlighting some of the indicators of hereditary CRC that are described above.) Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC.[37]

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Identification of Individuals at High Genetic Risk of CRC

National Comprehensive Cancer Network (NCCN) guidelines are updated annually to help identify patients who are appropriate for referral to cancer genetic counseling services. Furthermore, NCCN also provides cancer surveillance recommendations for hereditary cancer syndromes. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors have published a comprehensive set of personal/family history criteria to help identify at-risk individuals for referral to cancer genetics risk consultations.[51] These practice guidelines consider tumor types, other specific tumor features, and related criteria that would prompt a genetics referral. The authors state that these guidelines from ACMG/NSGC are intended to maximize referral of appropriate at-risk individuals to cancer genetic counseling services, but they are not meant to provide genetic testing or treatment recommendations. In addition, the authors note other sources that discuss updated/evolving genetic testing criteria for hereditary cancer syndromes (e.g., NCCN), and they acknowledge the increasing role of nongenetics professionals in facilitating genetic testing, especially to guide cancer treatment.[52]

When such persons are identified, options tailored to the patient situation are considered. (Refer to the Major Genetic Syndromes section of this summary for information on specific interventions for individual syndromes.)

At this time, the use of pathogenic variant testing to identify genetic susceptibility to CRC is not recommended as a screening measure in the general population. The rarity of pathogenic variants in CRC-associated genes and the limited sensitivity of current testing strategies render general population testing potentially misleading and not cost-effective.

Rather detailed recommendations for surveillance in FAP and Lynch syndrome have been provided by several organizations representing various medical specialties and societies. These organizations include the following:

The evidence bases for recommendations are generally included within the statements or guidelines. In many instances, these guidelines reflect expert opinion resting on studies that are rarely randomized prospective trials.

Difficulties in Identifying a Family History of CRC Risk

The accuracy and completeness of family history data must be considered when using family history to assess individual risk in clinical practice and when identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer.[62] Increased use of colonoscopy may result in fewer CRCs and more precancerous colon polyps in a family history. Individuals are much less likely to know about their family history of polyps (i.e., type of polyps and total number of polyps in their relatives) than they are to know about their family history of cancer. In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, due to incomplete penetrance, some individuals may carry a genetic predisposition to CRC but do not develop cancer, giving the impression of skipped generations in a family tree.

Accuracy of patient-reported family history of colon cancer has been shown to be good, but it is not optimal. Patient report should be verified by obtaining medical records whenever possible, especially for reproductive tract cancers that may be relevant in identifying risk of Lynch syndrome and less reliably reported by some patients. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Several approaches are available to evaluate a patient with newly diagnosed CRC who may or may not be suspected of having a cancer genetics syndrome. The clinician may suspect a potential inherited disposition based on the family history and physical exam, and genetic tests are available to confirm these suspicions. The American College of Medical Genetics and Genomics has published guidelines for evaluating patients with suspected colon cancer susceptibility syndromes.[51] The guidelines aim to identify individuals whose clinical features warrant referral for genetics consultation. If an individual has multiple polyps (>20), depending on the histology, specific gene-directed testing can be a useful diagnostic tool. Similarly, if a patient’s clinical presentation is suspicious for Lynch syndrome, germline genetic testing can be directed towards this syndrome. However, diagnosis is more challenging when the clinical picture is less clear. Currently, tumor screening for Lynch syndrome is the most commonly accepted approach. However, increasingly, panels characterizing somatic variants in tumors are being utilized for a variety of clinical decisions.

A priori risk-assessment testing (which models risk based on a variety of factors, such as age at cancer onset and the spectrum of tumors in the family) may be an appropriate alternative in many cases. Application of such risk models does anticipate the use of multigene (panel) testing; however, their exact role remains to be established.

Molecular Events Associated With Colon Carcinogenesis

Much of our initial understanding of the molecular pathogenesis of CRC derived from rare hereditary CRC syndromes and revealed heterogeneity of CRC both molecularly and clinically. It is well accepted that most CRCs develop from adenomas. The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[63–65] Presently, CRC can be separated into three categories based on similar molecular genetic features, suggesting divergent pathways of tumorigenesis: chromosomal instability (CIN), MSI, and CpG island methylator phenotype (CIMP). The understanding of the molecular genetic pathways of colorectal tumorigenesis is still evolving, and each new level of understanding has occurred in the context of the preceding level of knowledge. In addition, these pathways emerged from important clinical and histological heterogeneity of colorectal polyps and cancers. Thus, the introduction below captures the chronological evolution of our current understanding of colorectal tumorigenesis.

Major Genes

Major genes are defined as those that are necessary and sufficient for disease causation, with important pathogenic variants (e.g., nonsense, missense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic variants in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize.[1] Historically, most major colon cancer susceptibility genes have been identified by linkage analysis using high-risk families; thus, these criteria were fulfilled by definition, as a consequence of the study design.

The functions of the major colorectal (CRC) cancer genes have been reasonably well characterized over the past decade.[2] Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for familial adenomatous polyposis (FAP), Lynch syndrome, and juvenile polyposis syndrome (JPS), among others. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.

De Novo Pathogenic Variant Rate

Until the 1990s, the diagnosis of genetically inherited polyposis syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate (de novo pathogenic variant rate) in these populations. Interestingly, FAP, JPS, Peutz-Jeghers syndrome, Cowden syndrome, and Bannayan-Riley-Ruvalcaba syndrome are all thought to have high rates of spontaneous pathogenic variants, in the 25% to 30% range,[3–5] while estimates of de novo pathogenic variants in the MMR genes associated with Lynch syndrome are thought to be low, in the 0.9% to 5% range.[6–8] These estimates of spontaneous pathogenic variant rates in Lynch syndrome seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%),[9–11] making the de novo pathogenic variant rate for Lynch syndrome seem quite low in contrast to the relatively high rates in the other polyposis syndromes.

Genetic Polymorphisms and CRC Risk

It is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes.[12] Based on epidemiological studies, the risk of colon cancer in a first-degree relative (FDR) of an affected individual can increase an individual’s lifetime risk of colon cancer 2-fold to 4.3-fold.[13] The relative risk (RR) and absolute risk of CRC for different family history categories is estimated in Table 1. In addition, the lifetime risk of colon cancer also increases in FDRs of individuals with colon adenomas.[14] The magnitude of risk depends on the age at diagnosis of the index case, the degree of relatedness of the index case to the at-risk case, and the number of affected relatives. It is currently believed that many of the moderate- and low-risk cases are influenced by alterations in single low-penetrance genes or combinations of low-penetrance genes.[15] Given the public health impact of identifying the etiology of this increased risk, an intense search for the responsible genes is under way.

Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in Lynch syndrome or FAP. However, in combination with other common genetic loci and/or environmental factors, variants of this kind might significantly alter CRC risk. These types of genetic variations are often referred to as polymorphisms. Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed disease-associated polymorphisms or functionally relevant polymorphisms. When such variation involves changes in single nucleotides of DNA they are referred to as single nucleotide variants (SNVs).

Several genome-wide association studies (GWAS) have been conducted with relatively large, unselected series of patients with CRC, who have been evaluated for patterns of polymorphisms in candidate and anonymous genes throughout the genome.[16–19] The use of genome-wide scans in thousands of CRC cases and controls has led to the discovery of multiple common, low-risk CRC SNVs, which can be found in the National Human Genome Research Institute GWAS catalog. For more information on GWAS, see Cancer Genetics Overview.

A goal of these studies has been to identify SNVs that may confer mildly increased CRC risks. This risk stratification could potentially enhance usability of CRC screening by influencing patient decision making regarding the ages to begin/end CRC screening and the amount of time between screening studies. There is increasing interest about using SNVs to expand germline risk assessment. This could be expanded from only searching for monogenic forms of CRC predisposition with high-/moderate-penetrance to searching for forms of CRC predisposition with polygenic risk, which may have broader applicability in the general population. Additionally, multiple studies have examined if polygenic risk scores (PRS) can be used to personalize CRC risk assessment in individuals with average risk of developing CRC.[20,21] While the growing body of data on CRC risk SNVs and PRS have been promising, PRS are not currently used in routine clinical settings and are not considered clinically actionable to guide the use of CRC screening procedures. Formal implementation studies are warranted to analyze how PRS can guide CRC risk assessment and screening in routine clinical care.

APC I1307K

The APC I1307K polymorphism deserves special mention, given that it is commonly identified in individuals of Ashkenazi Jewish ancestry undergoing multigene (panel) testing [22,23] and is associated with an increased risk of CRC; however, it does not cause colonic polyposis. The I1307K polymorphism occurs almost exclusively in people of Ashkenazi Jewish descent and results in a twofold increased risk of colonic adenomas and adenocarcinomas compared with the general population.[24,25] The I1307K polymorphism results from a transition from T to A at nucleotide 3920 in the APC gene and appears to create a region of hypermutability by virtue of the fact that this results in an A₈ microsatellite coding sequence.[24] Although clinical assays to assess for the APC I1307K polymorphism are currently available, the associated CRC risk is not high enough to support their routine use. Based on currently available data, it is not yet known whether the I1307K carrier status should guide decisions regarding the age to initiate screening, the frequency of screening, or the choice of screening strategy.

Introduction

Originally described in the 1800s and 1900s by their clinical findings, the colon cancer susceptibility syndrome names often reflected the physician or patient and family associated with the syndrome (e.g., Gardner syndrome, Turcot syndrome, Muir-Torre syndrome, Lynch syndrome, Peutz-Jeghers syndrome [PJS], Bannayan-Riley-Ruvalcaba syndrome, and Cowden syndrome). These syndromes were associated with an increased lifetime risk of colorectal adenocarcinoma. They were mostly thought to have autosomal dominant inheritance patterns. Adenomatous colonic polyps were characteristic of the first four, while hamartomas were found to be characteristic in the last three.

With the development of the Human Genome Project and the identification in 1990 of the adenomatous polyposis coli (APC) gene on chromosome 5q, overlap and differences between these familial syndromes became apparent. Gardner syndrome and familial adenomatous polyposis (FAP) were shown to be synonymous, both caused by pathogenic variants in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations due to an APC pathogenic variant at the 3’ or 5’ ends of the gene. MUTYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the pathogenic variants were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for carriers of pathogenic variants (refer to Table 3).

With these discoveries genetic testing and risk management became possible. Genetic testing refers to searching for variants in known cancer susceptibility genes using a variety of techniques. Comprehensive genetic testing includes sequencing the entire coding region of a gene, the intron–exon boundaries (splice sites), and assessment of rearrangements, deletions, or other changes in copy number (with techniques such as multiplex ligation-dependent probe amplification [MLPA] or Southern blot). Despite extensive accumulated experience that helps distinguish pathogenic variants from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance (VUS) that cannot be used for predictive purposes.

Familial Adenomatous Polyposis (FAP)

Introduction

By 1900, several reports had demonstrated that patients with a large number of polyps (later subclassified as adenomas) were at very high risk of CRC and that the pattern of transmission in families was autosomal dominant. In the 20th century, the adenoma-to-carcinoma progression was confirmed, and FAP was recognized as the prototypical model for this progression.[11] Classic FAP is characterized by numerous (hundreds to thousands) adenomatous polyps in the colon and rectum developing after the first decade of life (refer to Figure 3).

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There is also a subset of classic FAP that has an attenuated phenotype. AFAP is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.)

FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.[1,12,13] It is an autosomal dominant condition, and the reported incidence varies from 1 in 7,000 to 1 in 22,000 live births.[14] The presence of ethnic differences in the prevalence of FAP has been suggested [14] but a large study did not find significant differences in ethnic variation in more than 6,169 individuals with a personal and/or family history of CRC and polyps who were referred for genetic testing at a large reference laboratory.[15] Most cases of FAP result from pathogenic variants in the APC gene on chromosome 5q21. (Refer to the Genetics of FAP section of this summary for more information about the APC gene and genetic testing.)

In addition to a high risk of colon adenomas in FAP patients, various extracolonic manifestations have also been described, including upper gastrointestinal (GI) tract adenomas and adenocarcinomas; fundic gland stomach polyps; nonepithelial benign tumors (osteomas, epidermal cysts, dental abnormalities); desmoid tumors; congenital hypertrophy of retinal pigment epithelium (CHRPE); and malignant tumors (thyroid and brain tumors, hepatoblastoma). Refer to Table 4 for the risks of these extracolonic manifestations in FAP.

Table 4. Extracolonic Tumor Risks in Familial Adenomatous Polyposis

Malignancy	Relative Risk	Absolute Lifetime Risk (%)
Adapted from Giardiello et al.,[16] Jagelman et al.,[17] Sturt et al.,[18] Lynch et al.,[19] Bülow et al.,[20] Burt et al.,[21] and Galiatsatos et al.[22]
aThe Leeds Castle Polyposis Group.
Desmoid tumor	852.0	15.0
Duodenal tumors and cancer	330.8	5.0–12.0
Thyroid cancer	7.6	2.0
Brain cancer	7.0	2.0
Ampullary cancer	123.7	1.7
Pancreatic cancer	4.5	1.7
Hepatoblastoma	847.0	1.6
Gastric cancer	Not defined	0.6a

FAP has also been known as familial polyposis coli or adenomatous polyposis coli (APC). Gardner syndrome was previously the diagnosis for FAP patients who manifested with colorectal polyposis, osteomas, and soft tissue tumors. However, Gardner syndrome has been shown genetically to be a variant of FAP, and thus the term Gardner syndrome is essentially obsolete in clinical practice.[23]

Attenuated Familial Adenomatous Polyposis (AFAP)

MUTYH-Associated Polyposis (MAP)

MAP is an autosomal recessively inherited polyposis syndrome caused by pathogenic variants in the Mut Y homolog gene. The Mut Y homolog gene, which is known as MUTYH, was initially called MYH, but was subsequently corrected because the myosin heavy chain gene already had that designation. MUTYH is located on chromosome 1p34.3-32.1.[215] The protein encoded by MUTYH is a base excision repair glycosylase, which repairs one of the most common forms of oxidative damage. Over one hundred unique sequence variants of MUTYH have been reported. A founder pathogenic variant with ethnic differentiation is assumed for MUTYH pathogenic variants. In White populations of northern European descent, two major variants, Y179C and G396D (formerly known as Y165C and G382D), account for 70% of biallelic pathogenic variants in MAP patients; 90% of these patients carry at least one of these pathogenic variants.[216] Other causative variants that have been found include P405L (formerly known as P391L) (Netherlands),[217,218] E480X (India),[219] Y104X (Pakistan),[220] 1395delGGA (Italy),[221,222] 1186-1187insGG (Portugal),[223] and p.A359V (Japan and Korea).[224–226]

The MUTYH gene was first linked to polyposis in 2002 in three siblings with multiple colonic adenomas and CRC but no APC pathogenic variant.[112] MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and Lynch syndrome.[227] MAP patients tend to develop fewer adenomas at a later age than patients with APC pathogenic variants [228,229] but still carry a high risk of CRC (35%–75%).[7,230,231] A 2012 study of colorectal adenoma burden in 7,225 individuals reported a prevalence of biallelic MUTYH pathogenic variants of 4% (95% CI, 3%–5%) among those with 10 to 19 adenomas, 7% (95% CI, 6%–8%) among those with 20 to 99 adenomas, and 7% (95% CI, 6%–8%) among those with 100 to 999 adenomas.[116] This broad clinical presentation results from the MUTYH gene’s ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with an FAP phenotype and without a detectable APC germline pathogenic variant carry biallelic variants in the MUTYH gene.[7,219,229,232]

Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients.[233] The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC.[215] Clinical management guidelines for MAP recommend screening with high-quality colonoscopy and polypectomy every 1 to 2 years if fewer than 20 adenomas are found. Colonoscopy begins no later than age 25 to 30 years (although screening at a younger age may be considered based on family history).[123,214,230] Upper endoscopic surveillance begins at age 30 to 35 years.[214] (Refer to Table 8 for more information about available clinical practice guidelines for colon surveillance in MAP patients.) The recommended upper endoscopic surveillance interval can be based on the burden of involvement according to Spigelman criteria.[214] Total colectomy with ileorectal anastomosis or subtotal colectomy may be necessary for patients with MAP depending on overall polyp burden.[230,234]

Although MAP is the only known biallelic (recessive) adenoma cancer predisposition syndrome described to date, there are examples of biallelic cases presenting with childhood tumors in which MMR genes are involved. For more information, see the IHC in constitutional mismatch repair deficiency (CMMRD) syndrome section.

Table 8 summarizes the clinical practice guidelines from different professional societies regarding colon surveillance of biallelic MAP.

Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, thyroid, and skin cancers (melanoma, squamous epithelial, and basal cell carcinomas).[236,237] Additionally, noncancerous extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[221,229,237,238] Female MAP patients have an increased risk of breast cancer.[239] These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or Lynch syndrome.[240,241]

Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying biallelic MUTYH pathogenic variants and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.

The clinical phenotype of monoallelic MUTYH pathogenic variants is less well characterized with respect to incidence and associated clinical phenotypes, and its role in susceptibility to polyposis and colorectal carcinoma remains unclear. Approximately 1% to 2% of the general population carry a pathogenic variant in MUTYH.[7,112,229] A 2011 meta-analysis found that carriers of monoallelic MUTYH pathogenic variants are at modestly increased risk of CRC (odds ratio [OR], 1.15; 95% CI, 0.98–1.36); however, given the rarity of carriers of monoallelic pathogenic variants, they account for only a trivial proportion of all CRC cases.[243] A large study of 2,332 heterozygotes among 9,504 relatives of 264 CRC cases with a MUTYH pathogenic variant found that the risk of CRC at age 70 years was 7.2% for men and 5.6% for women, irrespective of family history. Among those with an FDR with a CRC diagnosis before age 50 years, the risk at age 70 years was 12.5% for men and 10% for women.[231] Caution should be exercised in the interpretation of this study as the vast majority of carrier status from this study was imputed and not based on genotype. The authors felt the risk for MUTYH heterozygotes with an FDR with CRC was sufficiently high to warrant more intensive surveillance than the general population (but the same as for anyone with an FDR with CRC diagnosed before age 50 y).[228,231]

MMR genes may interact with MUTYH and increase the risk of CRC. An association between MUTYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 pathogenic variants in carriers of monoallelic MUTYH pathogenic variants with CRC compared with noncarriers with CRC (11.5% vs. 0%; P = .037).[244] However, a German study failed to duplicate these findings.[245] Additionally, a larger study found no increased cancer risk for carriers of MMR pathogenic variants with a MUTYH variant compared with those with a MMR pathogenic variant alone.[246]

Lynch Syndrome

Genetics of Lynch syndrome

The genetics of both the tumor and the germline have an important role in the development and diagnosis of Lynch syndrome. Tumor DNA in Lynch syndrome–associated tumors exhibits characteristic MSI, and in these cases, there is typically loss of IHC expression for one or more of the proteins associated with the MMR genes. Molecular testing with MSI and/or IHC has been adopted as a universal screen for diagnosis of Lynch syndrome in newly diagnosed patients with CRC and endometrial cancer. IHC testing results can potentially direct gene-specific germline testing. Many genetic testing laboratories offer multigene (panel) tests that simultaneously test for pathogenic variants in all of the Lynch syndrome–associated genes (and often additional genes associated with inherited cancer susceptibility).

Genetic and molecular testing for Lynch syndrome

MSI

The presence of MSI in colorectal tumor specimens is a hallmark feature of Lynch syndrome and can be cause for suspicion of a germline pathogenic MMR gene variant. Microsatellites are short, repetitive sequences of DNA (mononucleotides, dinucleotides, trinucleotides, or tetranucleotides) located throughout the genome, primarily in intronic or intergenic sequences.[275,276] The term MSI is used when colorectal, endometrial, or metastatic tumor DNA [277] shows insertions or deletions in microsatellite regions when compared with normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic variants, germline variants, or epigenetic alterations.[278] In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all tumors with MSI and not all tumors with loss of protein expression on IHC will be microsatellite unstable.

Certain histopathologic features are strongly suggestive of MSI phenotype, including the presence of tumor-infiltrating lymphocytes (refer to Figure 4), Crohn-like reaction, mucinous histology, and histological heterogeneity.[279]

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Initial designation of a colorectal adenocarcinoma as microsatellite unstable was based on the detection of a specified percentage of unstable loci from a panel of three dinucleotide and two mononucleotide repeats that were selected at a National Institutes of Health (NIH) Consensus Conference and referred to as the Bethesda panel. If more than 30% of a tumor’s markers were unstable, it was scored as MSI-H; if at least one, but fewer than 30% of markers were unstable, the tumor was designated MSI-low (MSI-L). If no loci were unstable, the tumor was designated microsatellite stable (MSS). Most tumors arising in the setting of Lynch syndrome will be MSI-H.[280] The clinical relevance of MSI-L tumors remains controversial; the probability is very small that these tumors are associated with a germline pathogenic variant in an MMR gene.

The original Bethesda panel has been replaced by a pentaplex panel of five mononucleotide repeats,[280] which has improved the detection of MSI-H tumors.

(Refer to the Prognostic and therapeutic implications of MSI section of this summary for more information about the treatment implications of MSI testing.)

(Refer to the Universal tumor testing to screen for Lynch syndrome section of this summary for information about the utilization of MSI status in the diagnostic workup of a patient with suspected Lynch syndrome.)

IHC

IHC methods are cheaper, easier to understand, and more widely available as a surrogate for MSI and, for these reasons, have replaced polymerase chain reaction (PCR)–based MSI testing in most institutions. IHC is performed in the colorectal or endometrial tumor (or metastatic sites) [277] for protein expression using monoclonal antibodies for the MLH1, MSH2, MSH6, and PMS2 proteins. Isolated loss of expression of any one of these proteins may suggest which specific MMR gene is altered in a particular patient.[281–284] However, certain proteins can form heterodimers (or have other binding partners) and yield loss of two proteins expressed on IHC.

MSI can lead to nucleotide-pairing slippage (looping) in which single nucleotide mispairs are introduced. Heterodimers of MMR proteins are formed to identify the errors and bind the DNA at these sites.[278,285] For example, MSH2 protein complexes with MSH6 protein to form MutSα, which has the main ability to repair single base pair mismatches and single base pair loop-out lesions that can occur during the replication of a mononucleotide repeat sequence. In the absence of MSH6 protein, the MSH2 protein will dimerize with the MSH3 protein forming the MutSβ complex, which can trigger repair of larger loop-out DNA mismatches, but also has some overlapping activity to repair lesions usually repaired by MutSα.

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As a result, when the germline pathogenic variant is in the MSH2 gene, the tumor IHC may not express both MSH2 and MSH6, as the latter protein requires binding to MSH2 for stability. In this case, if no pathogenic variant is found in either gene, germline pathogenic variant testing for EPCAM should be considered if it was not already included. Approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 pathogenic variant identified will have germline deletions in EPCAM.[286] The latter mechanism accounts for approximately 5% of all Lynch syndrome cases.[286] A deletion of one exon 9 allele in the EPCAM (TACSTD1) gene, which is immediately upstream of MSH2‘s start site and in the same orientation, can lead to transcriptional read-through and methylation of the MSH2 promoter. This can lead to subsequent silencing of MSH2 in any tissue that expresses EPCAM. The presence of EPCAM pathogenic variants showing similar methylation-mediated MSH2 loss has been reported in numerous families.[287] On the strength of these observations, germline EPCAM testing is performed in patients with loss of MSH2 protein expression on IHC testing of their CRCs but who lack a detectable MSH2 germline pathogenic variant and is included with MSH2 testing in all colon cancer gene panels. For more information, see the EPCAM section.

In patients with no variants in any of these genes, tumor sequencing may reveal biallelic, somatic MSH2 variants. For more information, see the Somatic biallelic mismatch repair deficiency (sometimes called Lynch-like syndrome) section.

Similarly, the loss of MLH1 (either by germline pathogenic variant or hypermethylation of the MLH1 promoter) results in the absence of expression of both MLH1 and PMS2 proteins in the tumor. The most common abnormal IHC pattern for DNA MMR proteins in colorectal adenocarcinomas is loss of expression of MLH1 and PMS2. PMS2 and MLH1 function as a stable heterodimer known as MutLα. MutLα binds to MutSβ and guides excision repair of the newly synthesized DNA strand.[278] A functional defect in MLH1 results in degradation of both MLH1 and PMS2, while a defect in PMS2 negatively affects only PMS2 expression. Thus, a loss of MLH1 and PMS2 indicates that there is an alteration in MLH1 (promoter hypermethylation or germline variant), while loss of PMS2 expression often indicates that there is a germline PMS2 variant. However, among 88 individuals with PMS2-deficient CRC, PMS2 germline pathogenic variant testing followed by MLH1 germline pathogenic variant testing revealed pathogenic PMS2 variants in 49 individuals (74%) and MLH1 pathogenic variants in 8 individuals (12%).[288] Eighty-three percent of the alterations in MLH1 were missense variants, but two relatives carried identical MLH1 variants, and one individual, who developed two tumors with retained MLH1 expression, carried an intronic variant that led to skipping of exon 8.[288] Therefore, in CRCs with solitary loss of PMS2 expression, an MLH1 germline pathogenic variant should be sought if no PMS2 germline variant is found. Tumors with MSI and loss of MSH2 and MSH6 protein expression are generally indicative of an underlying MSH2 germline variant (inferred MSH2 pathogenic variant). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter.

Unlike MLH1 and MSH2 (which both dimerize with other proteins or have other binding partners), germline pathogenic variants in MSH6 and PMS2 result in the isolated loss of those specific proteins by IHC. However, tumors from MSH6 pathogenic variant carriers may not display the MSI phenotype at a frequency as high as MLH1 and MSH2 carriers (despite an inactive DNA MMR system), as there are pathogenic missense variants that do not completely abrogate protein expression yielding false negative results by IHC testing.[267,289] In a study that reported tumor testing results among MMR germline carriers enrolled through the Colon Cancer Family Registry, 7 of 24 carriers (28%) with MSH6 pathogenic variants had tumors that displayed normal protein expression on IHC staining. IHC tumor testing was more informative for MLH1 and MSH2 pathogenic variant carriers in which 93% of MLH1 carriers had correlating loss of MLH1 protein expression and 96% of MSH2 carriers had loss of MSH2 protein expression.[267]

In some cases, tumors manifest MSI and/or IHC shows loss of DNA MMR protein expression, but no germline pathogenic variant is identified. This tumor phenotype is predominantly due to biallelic somatic inactivation of the DNA MMR genes and is not a pathogenic germline alteration. This phenomenon has been labeled Lynch-like syndrome (sometimes called LLS in the literature), although this terminology may cause confusion since this term represents a mechanism of sporadic carcinogenesis, rather than a stand-alone genetic syndrome. For more information, see the Somatic biallelic mismatch repair deficiency (sometimes called Lynch-like syndrome) section.

Table 9. Protein Loss and Potential Germline Defect(s)

Loss of Protein Expression	Germline MMR Defect Predicted by IHC Protein Expression Loss
	MLH1	MSH2	MSH6	PMS2	EPCAM
IHC = immunohistochemistry; MMR = mismatch repair.
MLH1/PMS2	X
MSH2/MSH6		X			X
MSH6			X
PMS2	X			X
MLH1	X			X
MSH2		X	X

Somatic MLH1 hypermethylation

It is important to recognize that hypermethylation of the MLH1 promoter, a somatic event confined to the tumor, can lead to abnormal protein expression of MLH1 on IHC. Approximately 10% to 15% of sporadic CRC cases have a microsatellite unstable tumor phenotype due to MLH1 hypermethylation and are not heritable. These sporadic MSI colon cancers [290] have a generalized excess of DNA methylation referred to as CIMP.[291] (Refer to the CIMP and the serrated polyposis pathway section in the Introduction section of this summary for more information.) Because loss of MLH1 protein expression on IHC occurs in both Lynch syndrome and sporadic tumors, its specificity for predicting germline MMR gene variants is lower than for the other MMR proteins, and additional molecular testing is often necessary to clarify the etiology of MLH1 absence.

BRAF pathogenic variants have been detected in 68% of CRC tumors with MLH1 promoter hypermethylation and very rarely, if ever, in CRC from patients with Lynch syndrome.[292–295] This suggests that detection of somatic BRAF V600E variant detection in CRC may be useful in excluding individuals from germline variant testing. As a result, BRAF V600 testing and/or MLH1 hypermethylation assays are increasingly used in universal Lynch syndrome–testing algorithms in an attempt to distinguish between an absence of MLH1 protein expression caused by hypermethylation and germline MLH1 pathogenic variants. Making such a distinction is also a more cost-effective approach in excluding individuals from germline testing.

Somatic biallelic mismatch repair deficiency (sometimes called Lynch-like syndrome)

Prior to the widespread use of somatic tumor sequencing, somatic MLH1 hypermethylation was thought to be the only major sporadic pathway for a tumor to have MSI-H/MMR-deficient (MMR-D) biology. It was presumed that any MSI-H/MMR-D CRC or endometrial cancer with patterns of MMR deficiency (other than MLH1/PMS2 loss) was due to Lynch syndrome, even if a germline pathogenic variant in an MMR gene could not be identified. However, as IHC is more routinely performed for all CRCs and endometrial cancers, it has become clear that other patterns of MMR deficiency can arise via sporadic mechanisms, typically by somatic biallelic MMR gene inactivation.[296] This phenomenon has been labeled Lynch-like syndrome (sometimes called LLS in the literature), although this terminology may cause confusion since this term represents a mechanism of sporadic carcinogenesis, rather than a stand-alone genetic syndrome.

Work from the Ohio Colorectal Cancer Prevention Initiative found that 88.4% of CRCs and 100% of endometrial cancers with unexplained MMR-D statuses (i.e., cancers did not have a germline pathogenic variant in an MMR gene or MLH1 promoter hypermethylation) had somatic biallelic MMR deficiency found on somatic tumor sequencing.[297,298] In an additional series of MMR-D cancers (mostly CRCs and endometrial cancers) that underwent paired germline and somatic MMR variant analyses, somatic biallelic genetic alterations were found in 49% of the tumors that lacked causal germline pathogenic variants, MLH1 promoter hypermethylation, and BRAF V600E variants.[299]

When CRCs, endometrial cancers, or other tumors have unexplained MMR-deficiency, in which somatic sequencing fails to identify somatic biallelic MMR deficiency, it is possible that a small fraction of these cases could represent occult Lynch syndrome (or other forms of unidentifiable inherited cancer risk). In these cases, it is recommended that patients’ clinical and family histories be carefully examined for possible inherited cancer risk. This will help determine if patients and their families will be clinically managed as if they have suspected Lynch syndrome. In these cases, careful scrutiny of any germline MMR gene VUS is also warranted to assess whether these VUSs could harbor pathogenicity. For more information about VUS genetic test results, see the Value of testing an affected family member first section in Cancer Genetics Risk Assessment and Counseling.

Some studies have attempted to define the risk of CRC and other Lynch syndrome–associated malignancies in cohorts of individuals with Lynch-like syndrome. However, the ability to clinically interpret these data may be limited since these populations presumably include a mix of individuals with sporadic MMR-D cancers and others with inherited cancer risk.[300,301]

IHC in constitutional mismatch repair deficiency (CMMRD) syndrome

In contrast with Lynch syndrome (which is defined by the presence of a single, germline, heterozygous, deleterious variant in an MMR gene), rarely, individuals can have deleterious germline variants in both alleles of the same MMR gene. These cases can present with homozygous or compound heterozygous genotypes. This is termed biallelic mismatch repair deficiency (BMMRD) or constitutional mismatch repair deficiency (CMMRD). The likelihood of CMMRD involving homozygous MMR gene pathogenic variants will inevitably be higher among consanguineous unions. Rates of consanguinity may be higher in rural and geographically and/or culturally isolated populations.[302]

Tumor studies yield characteristic abnormalities. In a series of 28 patients with CMMRD,[115] 17 brain tumors showed loss of staining for MMR protein in normal stromal cells and in neoplastic cells. This differs from tumors in patients with Lynch syndrome, in which normal staining is retained in nontumor cells. In contrast to this characteristic feature seen with IHC, PCR-based MSI analysis was not reliable, as 20 of 28 tumors from patients with CMMRD were MSS. Essentially all of the MSI-H tumors were colon cancers.

The PMS2 gene is markedly overrepresented in cases of CMMRD. It has been suggested that the presence of homozygosity in other MMR gene variants is a prenatally lethal state, while milder expression of PMS2 variants is consistent with survival when present in both parental alleles.

For more information about CMMRD’s clinical phenotype, see the CMMRD section.

Table 10. Hereditary Colorectal Cancer (CRC) Syndromes and Associated Tumor Phenotypesa

Clinical Phenotype	Pathogenic Germline Variant in DNA MMR	Somatic Inactivation of DNA MMR	Tumor Phenotype
CMMRD = constitutional mismatch repair deficiency; FCCX = familial colorectal cancer type X; MMR = mismatch repair; MSI = microsatellite instability; MSS = microsatellite stable.
aAdapted from Carethers et al.[301]
Lynch syndrome	Present in one allele	Present in one allele	MSI
Sporadic CRC with hypermethylation of MLH1 promoter	Absent	+BRAF	MSI
CMMRD	Present in two alleles	Absent	MSI (tumor and normal tissue)
Somatic biallelic MMR deficiency (sometimes called Lynch-like syndrome)	Absent	Present in two alleles	MSI
FCCX	Absent	Absent	MSS

Constitutional epimutation

While somatic hypermethylation of the MLH1 promoter is acquired and not uncommon, examples of MLH1 promoter hypermethylation have been described in the germline and are generally not associated with a stable Mendelian inheritance. This constitutional methylation of MMR genes occurs most often in MLH1 and, to a lesser extent, MSH2 and is termed constitutional epimutation.[303] A constitutional epimutation (also referred to as a primary epimutation) is an acquired alteration in normal tissue that silences an active gene or activates an inactive gene.[304] Such epimutations occur most often in maternal alleles. In some cases, all somatic cells appear involved, while in others there is evidence of mosaicism. Tumors in patients with primary epimutations are generally indistinguishable from those otherwise typical of Lynch syndrome germline variant carriers, including age at onset, tumor spectrum, and presence of abnormal MSI and IHC. Since these are not inherited in a Mendelian fashion, antecedent family history of tumors is minimal, and risk to offspring somewhat unpredictable. Epimutations present in a de novo case seem to typically be “erased” in the process of gametogenesis and to not be passed to the next generation. Very rare cases of inherited MLH1 epimutations have been reported.[305,306]

Interpreting molecular alterations in tumors and distinguishing the likely primary epimutation cases from those of sporadic MSI poses significant challenges. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1 promoter. Rare instances of a de novo constitutional epimutation in MLH1 [307] or an inherited germline MLH1 methylation [308] add some complexity to the interpretation of MSI associated with absence of MLH1 expression. Akin to sporadic MSI, primary epimutation tumors show methylation of the MLH1 promotor and may show BRAF variants as well. As noted above, family history of cancer in such cases tends to be minimal or absent, as in true sporadic MSI. Distinguishing such cases from sporadic cases may call for assaying normal tissue (e.g., blood or normal colon mucosa) for evidence of MLH1 methylation, which will be absent from true sporadic cases and absent from carriers of conventional Lynch syndrome MMR pathogenic variants.

Such MLH1-predominant primary epimutations are to be distinguished from secondary epimutations such as those occurring when MSH2 is methylated as a consequence of inherited variants in the upstream EPCAM gene. (Refer to the EPCAM section of this summary for more information.)

Molecular diagnostic tumor testing to screen for Lynch syndrome in clinical practice

While many molecular pathology laboratories can assess both MSI and IHC, an approach that uses IHC testing as the initial screen for defective MMR activity has been favored because it is less labor intensive and more cost-effective.[309,310] Part of this rationale is that the information provided by IHC may target germline genetic testing toward one specific MMR gene (with the exception of loss of MLH1 expression) as opposed to a comprehensive testing strategy of all Lynch syndrome–related MMR genes that would be directed by the use of MSI alone.[256,309,311–314] While MSI testing was originally favored in the oncologic evaluation of individuals with CRC for its prognostic and therapeutic implications, screening for Lynch syndrome can be more effectively directed by IHC testing.

Universal tumor testing to screen for Lynch syndrome

Use of MSI and/or IHC testing in all newly diagnosed cases of CRC, regardless of the age at diagnosis or family history of cancer, increases the sensitivity of the initial screen for Lynch syndrome. This approach is more sensitive than existing clinical criteria, as many individuals with Lynch syndrome are diagnosed at older ages (>50 y) and have less striking family histories of CRC than previously appreciated. This universal testing of colorectal (and endometrial) tumors using either MSI or IHC testing has been recommended by many professional organizations and is being widely adopted.[123,315–318]

Genetic risk assessment and MMR gene variant testing in individuals with newly diagnosed CRC can lead to improved outcomes for the patient and at-risk family members. Dating back to 2009, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC), reported that there was sufficient evidence to recommend offering tumor screening for Lynch syndrome to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives.[319,320] At that time, there was insufficient evidence to recommend a specific testing strategy between MSI and IHC.

Several studies have demonstrated the feasibility of universal screening for Lynch syndrome. Initial experience from one institution found that among 1,566 patients screened using MSI and IHC, 44 patients (2.8%) had Lynch syndrome. For each proband, an average of three additional family members were subsequently diagnosed with Lynch syndrome.[256] A subsequent pooled analysis of 10,206 incident CRC patients tested with MSI/IHC as part of four large studies revealed a pathogenic variant detection rate of 3.1%.[321] This study compared four strategies for tumor testing for the diagnosis of Lynch syndrome: (1) testing all individuals meeting at least one criterion of the Bethesda guidelines; (2) testing all individuals meeting Jerusalem recommendations;[322] (3) testing all individuals with CRC aged 70 years or younger, or older than 70 and meeting at least one criterion of the Bethesda guidelines; and (4) universal testing of all individuals with CRC.[321] Tumor testing with MSI involved panels individualized at each institution and IHC involved testing all four of the DNA MMR genes involved with Lynch syndrome, across all institutions. The strategy of tumor testing in all individuals diagnosed with CRC at age 70 years or younger and testing individuals over age 70 who met one of the revised Bethesda guidelines yielded a sensitivity of 95.1%, a specificity of 95.5%, and a diagnostic yield of 2.1%. This strategy missed 4.9% of Lynch syndrome cases, but 34.8% fewer cases required IHC/MSI testing, and 28.6% fewer cases underwent germline testing than in the universal approach.

The consideration to further stratify the recommendation for molecular tumor testing by age (i.e., 70 y) warrants attention as it influences the cost-effectiveness of universal screening strategy.

Loss of MLH1 and PMS2 due to somatic hypermethylation is not uncommon, and is more frequently detected with increasing age at CRC diagnosis.[323] Therefore, additional molecular tumor testing including BRAF and MLH1 hypermethylation testing is recommended in cases in which there is loss of MLH1 and PMS2 expression on IHC, thereby decreasing the number of individuals referred for unnecessary germline genetic testing. A testing strategy including MLH1 hypermethylation analyses in individuals aged 70 years or younger with CRC who had loss of MLH1 on IHC was shown to be cost-effective in a population-based study of 1,117 individuals.[324]

Screening individuals with CRC for Lynch syndrome is most often performed in a stepwise fashion based on IHC tumor testing results that evaluate protein expression for the four MMR genes related to Lynch syndrome. One proposed strategy is summarized in Figure 6. This framework does not incorporate a germline testing approach that simultaneously evaluates multiple cancer susceptibility genes (multigene [panel] testing), which may be useful in select patient populations. (Refer to the Multigene [panel] testing section of this summary for more information.)

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Clinicians are increasingly utilizing tumor sequencing to advance therapeutic decisions in a more personalized approach, particularly in patients with metastatic disease. The performance of next-generation tumor sequencing (NGS) of CRCs for the detection of Lynch syndrome was compared with existing screening protocols that include MSI testing and IHC staining (with BRAF p.V600E testing) in 419 CRC cases recruited in a multicenter, population-based study.[325] Twelve participants were identified as Lynch syndrome carriers by germline DNA testing and all were correctly identified by tumor sequencing, while MSI plus BRAF testing and IHC plus BRAF testing missed five and six Lynch syndrome cases, respectively. Tumor sequencing had a higher sensitivity than IHC plus BRAF testing (100% vs. 89.7%; P = .04) and MSI plus BRAF testing (100% vs. 91.4%; P = .07) while specificity was comparable across all strategies (95.3% for tumor sequencing, 94.6% for IHC plus BRAF, and 94.8% for MSI plus BRAF; P = not significant). In a validation cohort of 46 known Lynch syndrome pathogenic variant carriers with CRC, tumor sequencing yielded similar results and correctly identified 100% of carriers. In addition, the authors highlighted potential therapeutic implications by reporting on somatic alterations identified by tumor sequencing in 283 participants. This study suggested that tumor sequencing is a highly effective mode of identifying Lynch syndrome; however, the cost-effectiveness of this strategy remains to be determined.

A 2019 retrospective study using data from a large, community-based, integrated U.S. health care system compared the diagnostic performance of age-restricted screening strategies for Lynch syndrome by reflex MMR IHC of all CRCs versus a universal screening strategy without an upper age limit.[326] Lynch syndrome identification decreased substantially after age 70 years to age 75 years, with minimal incremental gain after age 80 years. The number of CRCs needed to be screened to identify one Lynch syndrome case was 20 among patients diagnosed with CRC at age 50 years or younger but increased to 208 for those with CRC at age 71 years to age 80 years, and 668 for those diagnosed after age 80 years.

Cost-effectiveness of universal tumor screening for Lynch syndrome

Results are available from a Markov model that incorporated the risks of colorectal, endometrial, and ovarian cancers to estimate the effectiveness and cost-effectiveness of strategies to identify Lynch syndrome among individuals aged 70 years or younger with newly diagnosed CRC.[310] The strategies incorporated in the model were based on clinical criteria, prediction algorithms, and tumor testing or up-front germline pathogenic variant testing followed by directed screening and risk-reducing surgery. IHC followed by BRAF pathogenic variant testing was the preferred strategy in this study. An incremental cost-effectiveness ratio of $36,200 per life-year gained resulted from this strategy. In this model, the number of relatives tested (3–4) per proband was a critical determinant of both effectiveness and cost-effectiveness. These results were similar to earlier analyses conducted by EGAPP which found that the most cost-effective approach was to test all tumors for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline testing of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF variant-negative tumors.[320]

NCCN 2024 guidelines support using universal screening on all CRCs to help identify individuals who may have Lynch syndrome. Universal screening can include the following testing methods: IHC testing, MSI testing, and comprehensive tumor NGS panel testing.[123] Universal screening in all individuals irrespective of age was associated with a doubling of incremental cost per life-year saved compared with screening only those younger than 70 years.[310] The authors of this analysis conclude that screening individuals younger than 70 years appears reasonable, while screening all individuals regardless of age might also be acceptable, depending on willingness to pay.

However, it is important to note that the conclusions from this study were contingent upon the number of at-risk relatives who underwent germline testing (through a process known as cascade screening) based on the identification of a germline MMR gene variant in the index case of CRC in the family. In their model, to meet the accepted $50,000 cost-effective threshold, testing a minimum of three to four relatives was necessary.[310] This emphasizes the importance of provider-to-patient communication, family communication, and the need to ensure improved uptake of germline testing in Lynch syndrome families with a known causative gene. (Refer to the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for more information about family communication and uptake of genetic testing in families with Lynch syndrome.)

Another study addressed the cost-effectiveness of testing for pathogenic variants in the Lynch syndrome–associated genes and evaluated 21 screening strategies, including clinical criteria, use of clinical Lynch syndrome prediction models, and molecular tumor testing.[327] The model included two steps: (1) measurement of the newly identified number of Lynch syndrome diagnoses; and (2) measurement of the life-years gained as a result of confirming Lynch syndrome in a healthy carrier. Among all of the strategies modeled, screening the proband with a predictive model such as PREMM(1,2,6) followed by IHC for MMR protein expression and germline genetic testing was the best approach, with an incremental cost-effectiveness ratio of $35,143 per life-year gained. Germline genetic testing on all probands was the most effective approach, but at a cost of $996,878 per life-year gained. The authors concluded that the initial step of Lynch syndrome screening should utilize a predictive model in the proband, and that both universal testing and general population screening strategies were not cost-effective screening strategies for Lynch syndrome.

Establishment of an upper age limit for universal tumor testing remains controversial. Some experts have endorsed testing only individuals with CRC who are younger than 70 years (reserving testing in individuals ≥70 y for only those meeting the revised Bethesda criteria; with this strategy, 5% of carriers would be missed).[328] However, others have advocated against an upper age limit for testing given the potential benefit to younger generations via cascade screening and the opportunity for increased surveillance and other prophylactic interventions in individuals found to carry a known familial pathogenic variant.

Another cost-effectiveness analysis was performed using data from 179 consecutive endometrial cancer patients diagnosed at or before age 70 years and screened with MMR IHC and reflex MLH1 promoter hypermethylation, among whom seven Lynch syndrome carriers (3.9%) were identified.[329] Only one of the seven Lynch syndrome probands was age 50 years or younger at endometrial cancer diagnosis. The authors calculated that screening women diagnosed with endometrial cancer at age 51 to 70 years resulted in an additional 29.3 life-years gained (on top of the 45.4 life-years gained by screening women diagnosed at age ≤50 y), and the incremental cost-effectiveness ratio for screening all diagnoses at age 70 years or younger versus diagnoses at age 50 years or younger was 5,252 euro per life-year gained. Universal tumor-based screening of all women aged 70 years or younger was also cost-effective, compared with strategies using the Bethesda guidelines to guide MMR and MSI testing with an incremental cost-effectiveness ratio of 6,668 euro per life-year gained.

The cost-effectiveness of universal tumor testing in both CRC and endometrial cancer is largely driven by the assumption of cascade screening through which other at-risk family members will be identified, tested, and subsequently pursue their own cancer risk reduction.[310]

The cost of germline genetic testing continues to decrease with advancements in DNA analyses, including simultaneous testing of multiple germline variants associated with malignancy, through multigene (panel) tests. As a result, additional cost-effective analyses using more updated data related to germline testing will need to be conducted. Multigene (panel) testing may become a more favorable and cost-effective approach in the future.

Considerations and limitations related to universal tumor testing for Lynch syndrome

While universal screening continues to be adopted nationally, there is significant variability in the uptake and approach to molecular testing. A 2011 survey of the National Society of Genetic Counselors revealed that more than 25% of respondents had some form of universal screening implemented at their center. Tumor screening methods varied; 34 (64.2%) of 53 centers started with IHC, 11 (20.8%) of 53 centers started with MSI testing, and 8 (15.1%) of 53 centers performed both tests on newly diagnosed colorectal tumors.[330] A 2012 survey suggested that some form of universal screening was being routinely performed at 71% of the National Cancer Institute (NCI) Comprehensive Cancer Centers, but utilization dropped to 15% among a random sample of community hospital cancer programs.[331]

Because adherence to universal screening for Lynch syndrome may be poor (many patients are not referred for genetic evaluation and testing), a prospective quality improvement study utilizing the Six Sigma conceptual framework was conducted to improve the implementation of universal genetic screening among young patients with CRC.[332] The main aim of the study was to increase the proportion of tumor studies for deficient MMR among patients with early-onset CRC (aged 18–50 y). The intervention involved patient and provider education, in addition to visual cues provided at point of care. The study demonstrated an improvement of 21.5% in the rate of IHC testing in young adults with CRC over the 12-month postintervention period compared with the preintervention period.

Studies reporting uptake of genetic testing for Lynch syndrome have largely focused on individuals and families who were selected for potential risk of Lynch syndrome based on family history or clinical characteristics. While universal tumor screening is increasingly being adopted to identify newly diagnosed patients who may have a germline variant, few studies have examined the uptake of genetic testing after universal tumor testing. An important implication of universal screening for Lynch syndrome is that it does not result in automatic germline testing in appropriate individuals. In the clinical setting, more follow-up by health care teams to facilitate referral to genetic counseling for patients with abnormal tumor screening results may improve completion of genetic testing.[333] Higher levels of patient completion of genetic testing after abnormal tumor screening may be associated with having genetic counselors involved in this process to disclose screen-positive results, provide counseling after tumor testing, or facilitate referrals.[334]

Subsequent genetic counseling requires coordination between the pathologist, the referring surgeon or oncologist, and a cancer genetics service. As an illustration, a population-based screening study found that only 54% of patients with an IHC-deficient tumor (that was BRAF pathogenic variant negative) ultimately consented to and proceeded with germline MMR testing.[335] One institution found 21 pathogenic variants among 1,100 patients who underwent routine MSI and IHC testing after a diagnosis of CRC. This study found markedly increased uptake of genetic counseling and germline MMR gene testing when both the surgeon and a genetic counselor received a copy of abnormal MSI/IHC results, especially when the genetic counselor played an active role in patient follow-up.[333]

In contrast to tumor testing, which is commonly performed without a patient’s prior knowledge, germline genetic testing, such as germline testing for MMR pathogenic variants, generally includes genetic counseling and requires patient permission before it is performed. A cross-sectional survey of U.S. cancer programs (20 NCI–designated Comprehensive Cancer Centers and 49 community hospital cancer programs) found that, of those that performed MSI and/or IHC testing as part of standard pathological evaluation at the time of colon cancer diagnosis in all or select cases, none required written informed consent before tumor testing.[331]

Diagnostic strategies for all individuals diagnosed with endometrial cancer

Given the increased prevalence of endometrial cancer among carriers of MMR pathogenic variants, there is a growing consensus to screen patients with endometrial cancer for Lynch syndrome.

In a study that examined the feasibility and desirability of performing tumor screening of all endometrial cancers, regardless of age at diagnosis or family history of cancer, at least 2.3% (95% CI, 1.3%–4.0%) of newly diagnosed patients had Lynch syndrome.[336,337] Eight of thirteen cases diagnosed with Lynch syndrome were aged 50 years or older, eight did not meet published family history criteria for Lynch syndrome, and two would have been missed by MSI testing. Because of the increased prevalence of endometrial cancer and the results of this study, the authors support universal screening of endometrial cancers for Lynch syndrome. (Refer to the IHC section of this summary for more information about performing IHC for MMR protein expression.)

Another smaller study of 242 consecutive endometrial cases demonstrated a 4.5% (11/242) prevalence of MMR-deficient cases lacking somatic MLH1 promoter hypermethylation, including four cases (1.7%) with germline MMR variants, four cases (1.7%) with two somatic MMR alterations on NGS, and two cases (0.8%) with otherwise unexplained MMR-deficiency.[338] Such findings demonstrate that universal MMR tumor screening of endometrial cancers will identify individuals with underlying Lynch syndrome and a spectrum of non-Lynch syndrome cases with various forms of MMR-deficiency.

Another study prospectively evaluated universal IHC-based screening of both CRC and endometrial cancer cases, irrespective of age at diagnosis.[339] In both the tertiary and community settings, 1,290 CRC and 484 endometrial cancer cases were screened between 2011 and 2013. The study additionally calculated PREMM(1,2,6) and PREMM5 scores for all patients in whom a germline pathogenic variant was detected. Abnormal staining was observed in 22% of endometrial cancers and 18.8% of CRCs. After excluding those cases felt to be sporadic because of the presence of BRAF and/or hypermethylation of MLH1, 10.8 % of patients with CRC and 6.6% of patients with endometrial cancer were referred for genetic counseling. Lynch syndrome was diagnosed in 24 individuals (1.4%), 66% of whom had CRC. The overall detection rate of Lynch syndrome was 1.7% in endometrial cancer cases and 1.2% in CRC cases. Among Amsterdam criteria, Bethesda guidelines, PREMM(1,2,6), and PREMM5, the best performing model was PREMM5, which would have detected 82% of cases identified by universal screening.

The cost-effectiveness of tumor testing of women diagnosed with endometrial cancer was examined in a model-based simulation study and included IHC testing in the following scenarios: (1) diagnosis before age 50 years; (2) diagnosis before age 60 years; (3) any age at diagnosis with the presence of an FDR with any Lynch syndrome–associated cancer; and (4) all cases irrespective of diagnosis age and family history. Women fulfilling Amsterdam II criteria or those diagnosed before age 50 years with at least one FDR with any Lynch syndrome–associated cancer were directly referred for genetic counseling and genetic testing without IHC testing. A strategy of IHC testing for MMR protein expression in all patients with endometrial cancer and an FDR with any Lynch syndrome–associated cancer was reported to be cost-effective in the detection of Lynch syndrome.[340] This strategy had an incremental cost ratio of $9,126 per life-year gained relative to the least-costly strategy, which was genetic testing on all women diagnosed with endometrial cancer before age 50 years with at least one FDR with a Lynch syndrome–related cancer. Life expectancy was highest with the most inclusive testing strategy of IHC testing of all women with endometrial cancer irrespective of age at diagnosis or family history but had the least favorable incremental cost ratio of $648,494 per life-year gained. NCCN recommends tumor testing with IHC and/or MSI and a comprehensive tumor NGS panel testing for all endometrial cancers.[123] Despite these recommendations, the uptake of universal screening in women newly diagnosed with endometrial cancer is unclear.

(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about endometrial cancer as a component of Lynch syndrome.)

MSI in all cancers

Use of MSI testing across all tumor types has become an important screening tool to select cases that may have a favorable response to immune checkpoint inhibitor therapy. These results may potentially be used to screen for Lynch syndrome in tumors other than CRC. A study evaluated MSI across a wide variety of malignancies and evaluated its use as a potential means to identify Lynch syndrome, regardless of tumor type.[341] In a study of more than 15,000 patients with more than 50 types of cancers evaluated in a single-center study, data on well-annotated tumor and matched normal DNA sequencing results with paired germline MMR gene testing, were used to determine MSI status. MSI was determined using a software tool that reports the percentage of unstable microsatellites as a score from paired tumor-normal genome sequencing data and allows for comprehensive investigation of MSI sites simultaneously. The approach used has been reported to be more sensitive across cancers not typically screened for MMR-deficiency (dMMR) than MSI testing of five mononucleotide microsatellite foci using PCR.[342] CRC and endometrial cancer comprised the majority of cancers with MSI-H in this study, but 38% (125 of 326) of MSI-H tumors and more than 90% of those with intermediate-level MSI were other cancer types. Germline testing confirmed a diagnosis of Lynch syndrome in 16.3% and 1.9% of tumors with MSI-H and intermediate-level MSI, respectively, in addition to 0.3% of cases that lacked MSI. Importantly, half of all Lynch syndrome carriers with MSI-H/intermediate tumors had primary cancers other than CRC or endometrial cancer, with many malignancies not associated with Lynch syndrome. Among those individuals with a noncanonical Lynch syndrome cancer, nearly half failed to meet clinical criteria for Lynch syndrome testing on the basis of their cancer diagnosis or family cancer history. Furthermore, intermediate-level MSI and MSS phenotypes were most often observed in cancers not classically related to Lynch syndrome and in individuals with germline PMS2 variants. This study supports other findings related to the variable phenotypic expression of Lynch syndrome on the basis of the altered MMR gene and its broad constellation of associated malignancies that make it difficult to be identified by clinical criteria alone. In addition, the investigators further analyzed a unique gene variant signature in every tumor and correlated results to the observed MSI phenotype and germline MMR status to provide some indirect data on whether a gene variant carrier’s cancer was caused by Lynch syndrome and MMR deficiency or possibly an incidental finding. This is pertinent in evaluating those cancers whose association with Lynch syndrome is unclear and debatable, such as breast and prostate cancer. The authors’ finding that none of the breast cancer patients with Lynch syndrome in this very large cohort had tumors with MSI lends support to the hypothesis that these individuals’ germline MMR gene variants may simply be incidental findings and not etiologic to their cancer diagnosis.

A single-institution study of 100 histologically confirmed small bowel adenocarcinomas with MSI/MMR tumor studies identified 26 cases with MMR deficiency, 10 of which were due to Lynch syndrome. Most cancers were located in the duodenum, followed by the jejunum and the ileum. The authors recommended that individuals with small bowel adenocarcinomas be screened for Lynch syndrome, given the implications of MMR deficiency on treatment and clinical management.[343]

Germline genetic testing

Genetic testing for germline pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM can help formulate appropriate intervention strategies for the affected variant-positive individual and at-risk family members, many of whom may be unaffected by cancer.

If a pathogenic variant is identified in an affected person, then testing for that same pathogenic variant should be offered to all at-risk family members. At-risk relatives who test negative for the identified pathogenic variant in the family are not at increased risk of CRC or other Lynch syndrome–associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial pathogenic variant are referred to surveillance and management guidelines for Lynch syndrome. (Refer to the Management of Lynch syndrome section of this summary for more information.)

If no pathogenic variant is identified in the affected family member, then testing is considered negative for Lynch syndrome in that individual. With advances made in DNA sequencing technologies, it is unlikely that current gene testing is not sensitive enough to detect a pathogenic variant in the genes tested. Advances in testing, including the common use of NGS by most commercial testing laboratories have improved upon the detection of certain alterations such as large deletions or genomic rearrangements as well as the presence of a pseudogene PMSCL in PMS2.

Possible reasons why a pathogenic variant may not be detected include the following:

• The family could have a variant in a yet-unidentified gene that causes Lynch syndrome or a predisposition to colon cancer.
• The individual tested in the family may have developed colon cancer through a nongenetic mechanism (i.e., it is a sporadic case also known as a phenocopy), while the other cases in the family are really the result of a germline variant. If this scenario is suspected, testing another affected individual who has had a Lynch syndrome–associated cancer is recommended.
• In cases in which a CRC tumor displayed MSI and/or abnormal IHC, but no germline pathogenic variant was detected, biallelic somatic variants may be the resulting etiology. These are sometimes, confusingly, called Lynch-like syndrome cases, even though they are typically not considered to be familial.

Failure to detect a pathogenic variant could mean that the family truly is not at genetic risk despite a clinical presentation that suggests a genetic basis (e.g., the patient may have biallelic somatic variants in an MMR gene). If no variant can be identified in an affected family member, testing should not be offered to at-risk members because results would be uninformative for the relatives. They would remain at increased risk of CRC by virtue of their family history and should continue with recommended intensive screening.

(Refer to the Management of Lynch syndrome section of this summary for more information.)

Multigene (panel) testing

Germline variant analysis of MLH1, MSH2 (including EPCAM), MSH6, and PMS2 may be considered in instances in which tumor tissue is not available from individuals to test for MSI and/or MMR protein IHC. This approach has become less expensive with the advent of multigene (panel) testing, which is now offered by several clinical laboratories at a cost that may be comparable to single-gene testing. The cost of multigene testing may also approach the cost of tumor screening and may prove to be a cost-effective approach in individuals affected by CRC. At present, multigene tests are not routinely recommended for universal screening for Lynch syndrome among all newly diagnosed CRC patients, but they may be very useful in select populations, such as those with early-onset CRC [344] or from familial, high-risk clinic-based populations. It is also important to note that pathogenic variants may be detected in other cancer-associated genes beyond Lynch syndrome. In a study of 1,112 individuals who met NCCN criteria for Lynch syndrome testing and who underwent multigene testing with a 25-gene panel, as expected, 114 individuals (9.0%) were found to have pathogenic variants in MMR genes; however, 71 individuals (5.6%) were found to have a pathogenic variant in non-Lynch syndrome cancer predisposition genes, such as BRCA1, BRCA2, APC, MUTYH (biallelic), and STK11. Lastly, multigene tests yield a high proportion of VUS. In the aforementioned study, a total of 479 patients (38%) had one or more VUS.[345]

Individuals with early-onset CRC have been shown to have a high frequency and wide spectrum of germline pathogenic variants, indicating that panel testing in this population may be beneficial. In a study of 450 patients with early-onset CRC (mean age at diagnosis, 42.5 y) and a family history including at least one FDR with colon, endometrial, breast, ovarian, and/or pancreatic cancer, 75 germline pathogenic or likely pathogenic variants were identified in 72 patients (16%).[344] The spectrum of variants identified included Lynch syndrome and non-Lynch syndrome–associated genes, including several genes that have not traditionally been associated with CRC (e.g., BRCA1/BRCA2, ATM, CHEK2, PALB2, and CDKN2A). Given the high frequency and variety of hereditary cancer syndromes identified, the authors suggested that multigene testing in this population may be warranted. Similarly, another smaller single-institution analysis of 151 individuals with CRC identified pathogenic germline variants in 9.9% of individuals.[346]

Multigene testing has also been examined in a larger study of 1,058 individuals with CRC who were unselected for age at diagnosis, personal or family history, or MSI/MMR test results.[347] Germline pathogenic variants in cancer susceptibility genes were identified in 105 individuals (9.9%). While 33 individuals (3.1%) carried pathogenic variants in Lynch syndrome genes, 74 (7.0%) had pathogenic variants in non-Lynch syndrome–associated genes, including APC, MUTYH, BRCA1/BRCA2, PALB2, CDKN2A, TP53, and CHEK2. These data illustrate the breadth of variants that may be identified in unselected CRC patients; thus, use of a comprehensive multigene test may be warranted.

A 2017 study examined the frequency of pathogenic Lynch syndrome–associated gene variants in individuals undergoing multigene testing at a single commercial United States laboratory between 2012 and 2015, and reported on the characteristics of those carriers identified with Lynch syndrome.[348] The study reports on the largest cohort of individuals tested through multigene testing to date; data was reported on 34,980 individuals who had undergone various multigene panel tests that included the MMR and EPCAM genes, where the indication for testing was not limited to Lynch syndrome. A total of 618 pathogenic variants were identified in 612 individuals (1.7%) and analyses were conducted on 579 subjects (after exclusion of 33 individuals who had a Lynch syndrome–associated variant and a second MMR variant or other pathogenic alteration in another cancer predisposition gene). The majority of carriers were affected by cancer, including non-Lynch syndrome–associated malignancies, where breast cancer was most frequently reported (124/423, 23.5%). MSH6 variants were most prevalent (29.3%), followed by PMS2 (24.2%), MSH2 (23.7%), MLH1 (21.6%), and EPCAM (1.2%). This finding differs from previous data where MSH2 and MLH1 variants were more prevalent, as individuals were more often selected for Lynch syndrome–specific testing due to a personal and/or family history of CRC.

The study reports on genotype-phenotype correlations on 528 Lynch syndrome carriers, the majority of whom had CRC (186, 35.2%) and endometrial cancer (136, 25.8%), followed by breast cancer (124, 23.5%) and ovarian cancer (74, 14%).[348] One hundred forty-five carriers presented with breast or ovarian cancer as their sentinel tumor and did not carry a prior diagnosis of CRC or endometrial cancer prior to the time of multigene testing. When examining MMR gene variant distribution among tumor-specific subgroups, a higher frequency of MSH6 and PMS2 variants were detected in carriers with breast cancer only than MLH1 and MSH2, where the latter pathogenic variants were more frequent in subjects with CRC only. For patients with breast cancer only, the frequency of PMS2 gene variants was significantly higher than population estimates, which was not the case for MLH1, MSH2, or MSH6. A comparable retrospective study reported similar findings. Standardized incidence ratios (SIRs) of breast cancer were calculated by comparing observed breast cancer frequencies in a population of 423 women with pathogenic or likely pathogenic variants in MMR genes with those in the general population. The authors reported a statistically significant age-standardized risk of breast cancer for MSH6 carriers (SIR, 2.11; 95% CI, 1.56–2.86) and PMS2 carriers (SIR, 2.92; 95% CI, 2.17–3.92).[349] A critical limitation of both of these studies was the excess of breast cancer cases in the overall referral population as well as the known high background population prevalence of MSH6 and PMS2 germline pathogenic variants.

Clinical criteria for the identification of Lynch syndrome, including the Amsterdam criteria, revised Bethesda guidelines, or the PREMM(1,2,6) risk prediction model, would have failed to identify 27.3% of Lynch syndrome carriers in this study.[348] Given the increased prevalence of breast and ovarian cancers, 58.9% met the NCCN guidelines for BRCA1/BRCA2 testing and of these, 36.7% also met NCCN guidelines for Lynch syndrome testing. Lastly, there were limited data on tumor testing results, available only on 18.8% of pathogenic variant carriers, where results were often discordant with the altered gene, which was most often reported in MSH6 and PMS2 carriers. Results of this study support the use of multigene testing for Lynch syndrome and further study of the respective cancer risks, as current testing strategies limit identification of Lynch syndrome carriers and associated malignancies.

Lastly, germline MMR genes have been detected unexpectedly among individuals undergoing multigene testing for cancers not commonly associated with Lynch syndrome, such as breast and prostate cancer. As a result, the cancer spectrum associated with Lynch syndrome may be wider than previously appreciated. For more information, see the Breast cancer and Prostate cancer sections and Genetics of Prostate Cancer.

(Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations, and research examining the use of multigene testing.)

Cost-effectiveness of multigene (panel) testing

As genetic testing becomes routine rather than the exception, questions regarding the cost of testing are inevitable. Historically, a cost-effectiveness ratio of $50,000 per quality-adjusted life-year (QALY) has been used as the benchmark for good value for care.[350] Over time it has been suggested that this threshold is too low and that other thresholds such as $100,000 or $150,000 be used.[350]

A 2015 study evaluated the cost-effectiveness of multigene testing for CRC and polyposis syndromes in patients referred to a cancer genetics clinic.[351] These authors developed a decision model to estimate the immediate and downstream costs for patients referred for evaluation and of CRC surveillance in family members identified as carriers of pathogenic variants. The costs were estimated on the basis of published models from the CDC and from an academic molecular genetics laboratory. They classified the syndromes on the basis of inheritance pattern and penetrance of CRC. Four custom panels were compared with the standard of care. The four panels tested for (1) Lynch syndrome–associated genes only (MLH1, MSH2, MSH6, PMS2, and EPCAM); (2) genes in panel 1 and additional genes associated with autosomal dominant inheritance and high CRC penetrance (APC, BMPR1A, SMAD4, and STK11); (3) genes in panels 1 and 2 and those associated with autosomal recessive inheritance with high CRC penetrance (MUTYH); or (4) all genes in the first three panels and those associated with autosomal dominant conditions with low penetrance (PTEN, TP53, CDH1, GALNT12, POLE, POLD1, GREM1, AKT1, and PIK3CA). The respective costs were as follows: panel 1, $144,235 per QALY; panel 2, $37,467 per QALY; panel 3, $36,500 per QALY; and panel 4, $77,300 per QALY when compared with panel 3. The authors concluded that the use of an NGS multigene test that includes highly penetrant CRC and polyposis syndromes and Lynch syndrome cancer genes was the approach most likely to provide clinically meaningful results in a cost-effective fashion.

The cost of germline genetic testing continues to decrease with advancements in technology since the time this model analysis was conducted; additional studies are needed to continue to assess the cost-effectiveness of this testing approach.

Hamartomatous Polyposis Syndromes

Hamartomatous polyposis syndromes are a distinct and rare group of polyposis diseases characterized by the presence of hamartomatous growths throughout the GI tract. Each syndrome manifests differently, depending on histological type, the number of GI polyps, the number of benign growths, GI cancer risks, and extra-GI cancer risks. Hamartomatous polyposis syndromes include the following:

Oligopolyposis

Oligopolyposis (derived from the Greek prefix, oligo, meaning few) describes polyp counts that are greater than anticipated in average-risk patients but are fewer than 100 polyps. Here, oligopolyposis is used to describe situations in which an individual’s polyp count is large enough to suspect a hereditary polyposis syndrome (generally between 10–100 polyps), regardless of the presence or lack of a family history of colorectal polyps/CRC. Since oligopolyposis specifically refers to polyp count, multiple syndromes can present with an oligopolyposis phenotype. It is recommended that most individuals with oligopolyposis have germline genetic testing.[123] These individuals are managed with frequent endoscopic surveillance, based on their underlying hereditary syndrome or guided by their endoscopic presentation.

Multiple syndromes can present with oligopolyposis. These syndromes vary based on polyp histology and the pathogenic variant that is identified. FAP is the most well-described adenomatous polyposis syndrome that occasionally presents with fewer than 100 tubular adenomas. Since the APC gene was discovered in 1992 (pathogenic variants in APC cause FAP), other rare genes have also been implicated in oligopolyposis and cancer. These genes include NTHL1, POLE/POLD1, GREM1, MUTYH, and AXIN2. The hamartomatous polyposis syndromes and serrated polyposis syndrome (SPS) are nonadenomatous polyposis syndromes that can present with oligopolyposis. Individuals with adenomatous polyposis who do not have an identified germline pathogenic variant have colonic adenomatous polyposis of unknown etiology (CPUE).

In a cross-sectional study of 3,789 patients with 10 or more colorectal polyps, patients underwent multigene panel testing for the following genes: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53. In this study, pathogenic variants were found in 5% of participants, regardless of the participant’s age or polyp cohort.[589] GREM1, POLD1, and POLE were only evaluated in 2,353 patients because these genes were added to the multigene panel assay during the study period. The number of pathogenic variants in adenomatous polyposis genes decreased as participants increased in age in all polyp-count groups in the adenoma cohort. This, however, was not true for the nonpolyposis-related CRC genes. The prevalence of pathogenic variants in hamartomatous polyposis genes was high in the hamartoma cohort, regardless of polyp count (40% of participants had 10–19 polyps, 72.1% of participants had 20–99 polyps, and 50% of participants had 100 or more polyps). The study provides additional support for multigene panel testing in individuals with 10 or more colorectal polyps, given that more than 5% of patients had pathogenic variants in all age groups. For more information about genetic testing for polyposis, see the Genetic testing for FAP section.

NTHL1, POLE, POLD1, and GREM1 pathogenic variant testing is being incorporated into the multigene panel tests for CRC susceptibility (offered commercially with APC and MUTYH testing so a polyposis panel can be ordered up front for patients with oligopolyposis). There are minimal data on the optimal surveillance approach for individuals with germline pathogenic variants in NTHL1 (biallelic carriers only), POLE, or POLD1. It is presumed that CRC risk for these pathogenic variants is comparable to that seen in Lynch syndrome. Hence, some guidelines are endorsing early and frequent colonoscopic screening, similar to that which is conducted in Lynch syndrome patients.

Lastly, oligopolyposis with varying polyp histologies (e.g., adenomas, serrated, inflammatory, and hamartomatous polyps) has been reported in two small case series of individuals previously treated with chemotherapy and radiation therapy for a prior childhood malignancy.[590,591] This phenomenon, termed therapy-associated polyposis (TAP), may be an acquired, nonfamilial phenotype caused by prior antineoplastic therapy. TAP is on the differential diagnosis list when nonfamilial oligopolyposis is identified in individuals previously treated with chemotherapy and/or radiation therapy. Another recent study identified oligopolyposis fulfilling World Health Organization (WHO) criteria for serrated polyposis syndrome (SPS) in 6% of a cohort of 101 Hodgkin lymphoma survivors treated with prior chemotherapy and/or radiation therapy.[592] This finding suggests that Hodgkin lymphoma survivors may be a particularly important population in TAP.

Polymerase Proofreading–Associated Polyposis (POLE and POLD1 Genes)

Pathogenic variants in related DNA polymerase genes, POLE and POLD1, have been described in families with oligopolyposis, CRC, and endometrial cancer. This condition is called polymerase proofreading–associated polyposis (PPAP).[593,594] PPAP is an autosomal dominant hereditary cancer syndrome, in which the main replicative DNA polymerases, POLE and POLD1, are unable to proofread newly synthesized DNA strands. Several other malignancies (including endometrial, ovarian, small bowel, and brain cancers), have also been described in POLE and POLD1 carriers. PPAP-associated tumors often present with an ultramutator phenotype characterized by mutational loads exceeding 100 variants per megabase. PPAP-associated cancers can be highly responsive to immune checkpoint inhibitor therapy, irrespective of MSI/MMR status.[595,596] Identifying POLE and POLD1 carriers can be challenging since all known, putative, causal POLE and POLD1 variants are exonuclease-domain missense variants, which are notoriously difficult to classify. In addition, studies on the prevalence and penetrance of PPAP are limited, since this condition is rare, and risk estimates may be subject to ascertainment bias.

The prevalence of POLE and POLD1 pathogenic variants was determined in a prospective cohort of 2,309 unrelated patients with hereditary cancer. These patients all underwent genetic testing with a multigene hereditary cancer panel, in which PPAP was responsible for 0.1% to 0.4% of familial cancer cases (and reaching 0.3% to 0.7% when only CRC and polyposis were considered).[597] The tumors most commonly associated with PPAP included CRC, endometrial cancer, and ovarian cancer.

While PPAP is rare, the age-specific cumulative risks (penetrance) of CRC for POLE and POLD carriers is important to quantify and update, in order to better guide and optimize clinical management. In a retrospective study in which families with POLE or POLD1 pathogenic variants were identified via a PubMed search of relevant studies (prior to 2016) and genotypic data from 669 population-based CRC cases diagnosed in patients under 60 (from the Australasian Colorectal Cancer Family Registry), age-specific cumulative risks were estimated using modified segregation analyses.[598] Sixty-seven CRCs were identified in 364 first-degree relatives (FDRs) and second-degree relatives (SDRs) in 41 POLE families, and 6 CRCs were identified in 69 relatives from 9 POLD1 families. CRC risk to age 70 years for males and females, respectively, was 40% (95% CI, 26%–57%) and 32% (95% CI, 20%–47%) in POLE carriers and 63% (95% CI, 15%–99%) and 52% (95% CI, 11%–99%) in POLD1 carriers. CRC risk for POLE carriers was high enough to consider annual colonoscopy screening and the possible implementation of management guidelines similar to those used in Lynch syndrome. The authors concluded that clinical management recommendations for POLD1 carriers could be similar to those used in POLE carriers, but refinement of POLD1 CRC risk estimates (from larger cohorts) are needed to further refine recommendations.

Lifetime risk estimates of CRC in POLE carriers were higher than expected in a subsequent study of 354 individuals with early-onset/familial CRC (n = 218) and/or attenuated adenomatous polyposis (n = 136) at a single center between 2014 and 2017.[599] In 51 POLE carriers (from 10 families), risk estimates for CRC and extracolonic PPAP-associated cancers were calculated using nonparametric methods (based on a survival analysis approach) to account for unknown genotypes in relatives. Risks of CRC at ages 30 years, 50 years, and 70 years were 11.1% (95% CI, 4.2–17.5), 48.5% (96% CI, 33.2–60.3), and 74% (95% CI, 51.6–86.1), respectively. These risk estimates were similar in both men and women. These results provided additional support for frequent CRC surveillance in POLE carriers, similar to the surveillance used in highly penetrant Lynch syndrome genotypes. Extracolonic cancers like glioblastoma, small bowel cancer, endometrial cancer, and ovarian cancer were observed at low frequencies, limiting the ability to establish screening recommendations for these cancer types.

In POLD1 and POLE carriers, NCCN recommends high-quality colonoscopy starting at age 25 to 30 years. Colonoscopy screening can also begin 2 to 5 years before the earliest CRC in the family, if the CRC was diagnosed before age 25 years. Afterwards, colonoscopy is repeated every 1 to 2 years if polyps are identified or every 2 to 3 years if polyps are not identified.[123] There is insufficient evidence to provide recommendations on extracolonic cancer prevention for patients with variants in these genes.

NTHL1-Associated Polyposis

NTHL1-associated polyposis (or NTHL1 tumor syndrome) was first described in 2015. A study used whole-exome sequencing in 51 individuals (from 48 families) with multiple colonic adenomas.[600] This study found homozygous germline nonsense pathogenic variants in NTHL1 (a base-excision repair gene) in seven affected individuals from three unrelated families. These individuals had CRC and multiple adenomas (8–50 adenomas). None of the adenomas were hyperplastic or serrated. Three affected females also had endometrial cancer or endometrial complex hyperplasia. One individual developed duodenal adenomas, and another individual developed duodenal cancer. All pedigrees were consistent with autosomal recessive inheritance. Three cancers and five adenomas from different affected individuals did not show MSI. These neoplasms did show enrichment of cytosine to thymine transitions.

A subsequent study of 863 families with CRC and 1,600 families without CRC confirmed an association between biallelic NTHL1 pathogenic variants and inherited CRC risk.[601]

In a systematic review of 21 papers, the phenotypic and genotypic spectrum of NTHL1 tumor syndrome, including the occurrence of both benign and malignant tumors, were reported in both biallelic and monoallelic carriers.[602]

Based on these results, the authors concluded that early endoscopic CRC surveillance can start before age 30 years in biallelic NTHL1 carriers, similar to the surveillance used in MUTYH carriers.[602] Given inconsistent reporting on duodenal polyposis and cancer in biallelic NTHL1 carriers, estimated duodenal neoplasia risk remains unclear, and upper GI tract surveillance could likely be postponed to the third or fourth decade of life. In addition, annual mammography or breast MRI can begin at age 40 years. However, this surveillance can begin at an earlier age if there is a young breast cancer diagnosis in the family. Gynecologic examination with TVUS can be considered every other year, starting at age 40 years.

Consistent with prior reports, monoallelic NTHL1 carriers do not have significantly increased cancer risk. It is not recommended, that these individuals undergo intensive cancer surveillance for GI, breast, or gynecologic cancers.

AXIN2-Related Polyposis

Pathogenic variants in AXIN2, a gene encoding a protein that forms part of the beta-catenin destruction complex, have been associated with oligodontia, ectodermal dysplasia, colorectal polyposis, and CRC in populations enriched with polyposis and CRC.[603,604] The beta-catenin destruction complex consists of several proteins, including AXIN2, and it downregulates beta-catenin, a transcriptional coactivator of Wnt-targeted gene expression.

The prevalence of AXIN2 pathogenic variants and their contribution to both colorectal polyposis and CRC remains unclear. An AXIN2 pathogenic variant was first implicated in a Finnish family (with multiple members) who had oligodontia (absence of >6 nonwisdom teeth in family members), CRC, and polyposis with autosomal dominant inheritance.[605] Subsequent reports had similar results, with other manifestations that included variable penetrance and ectodermal dysplasia (i.e., little hair and eyebrows).[606,607] Affected individuals with AXIN2 pathogenic variants from eight families in Australia/New Zealand were identified based on personal histories of unexplained colonic polyposis (presented with 10 to >100 colorectal polyps) and multiple CRC cases.[603] Similarly, 10 out of 11 French individuals with ten different AXIN2 pathogenic variants were ascertained based on histories of colorectal polyposis or CRC diagnosed at young ages. These individuals presented with adenomatous, serrated, and hyperplastic polyposis by a mean age of 55 years.[604] In three populations, extracolonic cancers included breast cancer, ampullary cancer, ovarian cancer, and melanoma. Multiple cases of tooth agenesis and ectodermal dysplasia (such as sparse hair and eyebrows) were frequently reported.[603,604]

In AXIN2 carriers, NCCN recommends the initiation of high-quality colonoscopy at age 25 to 30 years. Colonoscopy can be repeated every 2 to 3 years if polyps are not identified or every 1 to 2 years if polyps are found. Surgery can be considered in cases with unmanageable polyposis.[123] Given the lack of penetrance data for extracolonic cancers, no further recommendations are provided for AXIN2 carriers.

Hereditary Mixed Polyposis Syndrome (GREM1 Gene)

HMPS is a rare hereditary cancer syndrome characterized by the development of various types of colon polyps including serrated adenomas, atypical juvenile polyps, adenomas, and colonic adenocarcinoma. A small number of individuals/families with HMPS harbor a large, 40-kb, single-copy germline duplication upstream of gremlin 1 (GREM1)—the gene that is thought to cause the HMPS phenotype and increased CRC risk.[608]

Germline GREM1 pathogenic duplications have been observed primarily in individuals/families of Ashkenazi Jewish descent, with varying clinical presentations. Although polyposis appears to be a unifying feature in most families with this duplication, there is a high degree of variability with respect to polyp number, histology, and age of onset. In addition, extracolonic malignancies have been described in several GREM1 pathogenic variant carriers, although the small number of affected individuals limits the ability to definitively demonstrate a causal link to the GREM1 pathogenic variant.

Evidence-based strategies for managing individuals with germline GREM1 pathogenic duplications do not yet exist. However, NCCN guidelines recommend that GREM1 carriers initiate colonoscopic surveillance between ages 25 and 30 years.[123] Colonoscopy is repeated every 2 to 3 years if polyps are not identified or every 1 to 2 years if polyps are identified.

CHEK2

Several studies have suggested that germline CHEK2 pathogenic variants may confer increased risks

Natural History of Renal Cell Carcinoma

The natural history of each RCC syndrome is distinct and influenced by several factors, including histological features and underlying genetic alterations. Although it is useful to follow the predominant reported natural history of each syndrome, each affected individual must be evaluated and monitored for occasional individual variations. The individual prognosis depends on the characteristics of the renal tumor at the time of detection and intervention, which differs for each syndrome (VHL, HLRCC, HPRC, and BHD). Prognostic determinants at diagnosis include the stage of the RCC, whether the tumor is confined to the kidney, primary tumor size, Fuhrman nuclear grade, and multifocality.[14–16]

Family History as a Risk Factor for Renal Cell Carcinoma

Kidney cancer and renal pelvis cancer account for about 3.97% of all adult malignancies in the United States.[1] Epidemiological studies of RCC suggest that a family history of RCC is a risk factor for the disease.[4,17,18] An analysis of individuals with RCCs diagnosed before the year 2000 in the Sweden Family-Cancer Database included all Swedes born since 1931 and their biological parents. The study observed that the risk of RCC was particularly high in the siblings of those with RCC. Siblings of individuals with RCC had a higher relative risk (RR) than parent-child pairs.[17] Further work from this database confirms that 3% of individuals with RCC had a first-degree relative (FDR) with RCC.[19] Risk may be higher in individuals who have multiple FDRs with RCC and in women. Another study examined all patients in Iceland who developed RCC between 1955 and 1999 (1,078 cases). Investigators used an extensive computerized database to perform a unique genealogical study that included more than 600,000 Icelandic individuals. Results revealed that nearly 60% of Icelandic patients with RCC had a FDR or a second-degree relative (SDR) with RCC. Siblings of patients with RCC had an estimated RR of 2.5.[4] In a Korean study, individuals who had FDRs with RCC had a 2.29-fold increased risk of RCC. Risk did not appear to differ whether the FDR was a mother, father, or a sibling.[20] Modifying factors like obesity and hyperglycemia may further increase RCC risk in this high-risk population. Another study evaluated 80,309 monozygotic twins and 123,382 same-sex dizygotic twins in Denmark, Finland, Norway, and Sweden.[18] This study found excess cancer risk in twins whose co-twin was diagnosed with cancer. The estimated cumulative risks were an absolute 5% higher (95% confidence interval [CI], 4%–6%) in dizygotic twins (37%; 95% CI, 36%–38%) and an absolute 14% higher (95% CI, 12%–16%) in monozygotic twins (46%; 95% CI, 44%–48%)—for those whose co-twin also developed cancer—than in the overall cohort (32%). Overall heritability of cancer, calculated by assessing the relative contribution of heredity versus shared environment, was estimated to be 33%. Kidney cancer heritability was estimated to be 38% (95% CI, 21%–55%). Shared environmental factors did not significantly contribute to overall risk.

Young age at RCC onset is also a clue that hereditary etiology is possible. Unlike sporadic RCC, which is generally diagnosed during the fifth to seventh decades of life, hereditary forms of RCC are generally diagnosed at an earlier age. In a review of more than 600 cases of hereditary RCC from the National Cancer Institute, the median age of RCC diagnosis was 37 years, with 70% of cases being diagnosed at age 46 years or younger.[3] This age is lower than the median age of RCC diagnosis in the general population, which is 64 years.[21] Heritable RCCs are often multifocal and bilateral. A retrospective analysis of 1,235 patients with RCC who underwent genetic testing revealed that 6.1% of this population had positive genetic test results, 75.5% had negative test results, and 18.4% had a variant of unknown significance. Young age at RCC diagnosis was the only variable associated with a positive test result.[8] Other series showed that patients with non-clear cell advanced RCC may have an enrichment for pathogenic variants when compared with patients who had clear cell RCC; however, current research data are limited.[5,22]

While there is much debate about the referral criteria for hereditary RCC genetic testing, the following organizations have offered some guidance:

These guidelines acknowledge that the following criteria can prompt a referral to genetic counseling: early age of RCC onset, family history of RCC (≥1 FDR/SDR with RCC), bilateral or multifocal RCCs, and suspicious RCC histology. A consensus statement published by a group of kidney cancer experts provides additional guidance that may help providers identify patients who can be referred to genetic counseling.[25]

When evaluating patients at risk of hereditary kidney cancer, specific clinical features help determine which test is the most appropriate to order. Single gene tests are available during family variant testing or when there is only suspicion for one specific kidney cancer syndrome. The following panel tests are also available: 1) broad cancer genetic panels of up to 100 genes associated with cancer predisposition, and 2) renal cancer genetic panels with 15 to 20 genes that have strong associations with hereditary kidney cancer syndromes. Most of these panels conduct targeted sequencing of the exon with little coverage of the intron, except for splice-site variants. In the future, RNA testing may be useful to evaluate variants of unknown significance identified by DNA testing, to add additional support for pathogenicity. Whole genome sequencing (WGS) can be considered for rare cases with clinical suspicion that had negative panel testing. WGS may detect structural variants in introns that can contribute to cancer predisposition. In a series of over 1,300 unselected patients with RCC who underwent WGS, 6.9% of patients had germline pathogenic variants identified in cancer predisposition genes.[12]

Other Risk Factors for Renal Cell Carcinoma

Studies of environmental and lifestyle factors contributing to the risk of RCC focus almost exclusively on sporadic (i.e., nonhereditary) RCC. Smoking, hypertension, and obesity are the major environmental and lifestyle risk factors associated with RCC.[26] In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably resulting from somatic variants in the VHL gene.[27] Dietary intake of vegetables and fruits has been inversely associated with RCC. Greater intake of red meat and milk products have been associated with increased RCC risk, although not consistently.[28]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of renal cell carcinoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Renal Cell Carcinoma are:

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Renal Cell Carcinoma. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/kidney/hp/renal-cell-carcinoma-genetics. Accessed <MM/DD/YYYY>. [PMID: 26389510]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Incidence and Mortality

Transitional cell cancer of the renal pelvis accounts for only 7% of all kidney tumors, and transitional cell cancer of the ureter accounts for only 4% of upper urinary tract tumors. These cancers are curable in more than 90% of patients if they are superficial and confined to the renal pelvis or ureter. Patients with deeply invasive tumors that are confined to the renal pelvis or ureter have a 10% to 15% likelihood of cure. Patients with tumors with penetration through the urothelial wall or with distant metastases usually cannot be cured with available forms of treatment.

Prognosis

The major prognostic factor at the time of diagnosis of upper tract transitional cell cancer is the depth of infiltration into or through the uroepithelial wall.

Most superficial tumors are likely to be well differentiated, while infiltrative tumors are likely to be poorly differentiated. The incidence of synchronous or metachronous contralateral upper tract cancers ranges from 2% to 4%; the incidence of subsequent bladder cancer after previous upper tract transitional cell cancer ranges from 30% to 50%.[1] When involvement of the upper tract is diffuse (involving both the renal pelvis and ureter), the likelihood of subsequent bladder cancer increases to 75%. DNA ploidy has not added significant prognostic information beyond that provided by stage and grade.[2]

Diagnostics

Even if ureteroscopy and pyeloscopy are successfully implemented, accurate assessment of depth of invasion is difficult.

Treatment Management and Survivorship

Total excision of the ureter with a bladder cuff, renal pelvis, and kidney is recommended to provide the greatest likelihood of cure.

AJCC Stage Groupings and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define carcinoma of the renal pelvis and ureter.[6]

Patients may also be designated as having localized, regional, or metastatic disease, as follows:

Each of these classifications has been subclassified into categories of unicentricity or multicentricity. The latter category indicates a more pervasive tumor diathesis and generally a less favorable prognosis.

Although the classifications listed above have prognostic significance, they can be determined only at the time of nephroureterectomy, which is the treatment of choice for patients with this disease. Because of the high incidence of tumor recurrence within the intramural ureter among patients who have had incomplete excision of this area, nephroureterectomy includes the entire ureter and a margin of periureteral orifice mucosa (i.e., bladder cuff).

A TNM staging system has demonstrated accurate predictions of survival. The TNM staging system may be a better predictor of prognosis than tumor grade, although both are strongly predictive of survival. Median survival for patients with tumors confined to the subepithelial connective tissue was 91.1 months, compared with 12.9 months for patients with tumors invading the muscularis and beyond, in one report. Flow cytometry analysis identifies low-stage, low-grade tumors at high risk of recurrence by virtue of their aneuploid histograms.[7,8]

Treatment Options for Localized Transitional Cell Cancer of the Renal Pelvis and Ureter

Treatment options for localized transitional cell cancer of the renal pelvis and ureter include the following:

The development of new instrumentation for endourological treatment of upper tract transitional cell cancer has provided new options for regional management of these cancers. Introduction of electrofulguration and resection instruments or laser probes either transureterally or percutaneously, may permit destruction of a primary cancer. Introduction of cytotoxic agents has also been used. Although a biopsy can be taken for staging purposes, its accuracy remains to be determined. The efficacy of treatment by these maneuvers has not been established.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of transitional cell cancer of the renal pelvis and ureter. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment is:

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/kidney/hp/transitional-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389446]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.