The European Society for Clinical Oncology (ESMO) published an updated clinical practice guideline in August 2019 that provides individualized surveillance recommendations for patients with or at risk for hereditary gastrointestinal (GI) cancers.1 These cancers include colorectal cancer (CRC), gastric cancer, and pancreatic cancer.

Hereditary causes only constitute a small proportion of gastrointestinal cancers. For the majority of these hereditary syndromes, gene mutations that substantially increase the risk of developing GI or other cancers have been identified (Table). The goal of the updated ESMO guideline was to provide recommendations of optimal screening and diagnostic approaches and evidence-based prophylactic treatment related to each gene mutation or syndrome. Some syndromes increase the risk of multiple types of cancers but are associated with a predominant cancer type.

Table. Summary of Gene Mutations and Syndromes That Can Increase Cancer Risk

Gene Mutation Resulting Syndrome Potential Resulting Cancer(s)
MLH1, MSH2, MSH6, PMS2, EPCAM Hereditary non-polyposis colon cancer (or Lynch syndrome) CRC, endometrial cancer, ovarian cancer, gastric cancer, small bowel cancer, urinary tract cancer, pancreatic cancer, brain cancer, cutaneous gland cancer
APC Familial adenomatous polyposis CRC, gastric cancer, small bowel cancer, thyroid cancer
MUTYH MUTYH-associated polyposis CRC
POLE, POLD1 Polymerase proofreading–associated polyposis CRC
NTHL1 (16p13.3) Adenomatous polyposis associated with germline mutation in NTHL1 CRC
Unknown; potentially biallelic MUTYH or germline RNF-43 Serrated polyposis syndrome CRC
CDH1, CTNNA1 Hereditary diffuse gastric cancer Gastric cancer, lobular breast cancer
Promoter 1B of APC gene Gastric adenocarcinoma and proximal polyposis of the stomach Gastric cancer
Unknown; potentially BRCA1, BRCA2, PALB2, CDKN2A Hereditary pancreatic cancer Pancreatic cancer

Abbreviation: CRC, colorectal cancer.

Colorectal Cancer

The most common hereditary CRC syndrome is hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome, which accounts for approximately 1% to 3% of all CRC cases. HNPCC has autosomal dominance inheritance and is the result of mutations or epigenetic silencing of DNA mismatch repair genes. Depending on the specific gene affected, HNPCC increases the lifetime risk of CRC by 30% to 73%, endometrial cancer by 30% to 51%, and other cancers such as ovarian, gastric, small bowel, urinary tract, pancreatic, brain, and cutaneous gland tumors by 2% to 20%. The ESMO guideline recommends patients receive surveillance by colonoscopy every 3 years beginning at age 25 for MLH1 and MSH2 mutation carriers and age 35 for MSH6 and PMS2 mutation carriers, or 5 years prior to the age of onset in the youngest family member. Preventative CRC strategies include daily aspirin and lifestyle modification. The primary treatment of CRC among patients with HNPCC is extended colectomy and systemic therapies, such as immune checkpoint inhibitors.

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Up to 40% of families with an HNPCC-like syndrome do not harbor a mutation or deficiency in DNA mismatch repair genes. These families are recommended to undergo colonoscopy surveillance starting at age 40 or 10 years earlier than the age at which the youngest family member presented and every 3 to 5 years thereafter.

Another syndrome that increases the risk of CRC falls within the umbrella of hereditary polyposis colorectal cancer syndromes. This includes familial adenomatous polyposis (FAP), which is an autosomal dominant disorder caused by germline mutations in the APC gene. Family members with this mutation have a near 100% risk of developing early-onset CRC. Colonoscopic or flexible sigmoidoscopic surveillance is recommended to begin at age 12 to 15 and to be conducted every 2 years. However, once adenomas are detected, colonoscopy is recommended every 1 to 2 years until a colectomy is done. The ESMO guideline recommends that colectomy be performed before age 25. Prophylactic use of nonsteroidal anti-inflammatory drugs may reduce the number and extent of adenomas; however, cardiovascular side effects are possible and should be considered. In addition, it is recommended that patients undergo gastroduodenal endoscopy surveillance every 5 years beginning at age 25 to 30.

MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome that is the result of mutations within the MUTYH gene. The risk of developing CRC is increased by 19% at age 50 and 43% at age 60. It is recommended that colonoscopic surveillance in patients with MAP begin at age 18 to 20 and to occur every 1 to 2 years. Once polyps are too numerous for endoscopic removal, a colectomy or, for some patients, total proctocolectomy is recommended. Surveillance of patients with polymerase proofreading–associated polyposis or adenomatous polyposis syndrome associated with germinal mutation in NTHL1 is the same as for MAP.

The underlying mutation that results in serrated polyposis syndrome (SPS) is unknown, although mutations in the MUTYH or RNF-43 genes have been identified in some families. This syndrome increases the lifetime risk of CRC by 15% to 30%. ESMO recommends colonoscopic surveillance every 1 to 2 years. Total colectomy is preferred for patients who develop CRC or whose polyps cannot be successfully managed by endoscopy.