Hereditary Colorectal Cancer

About 10% of the general population has a first-degree relative with colorectal cancer (CRC); this history increases personal lifetime risk for CRC to 9% to 16%. Many guidelines recommend early screening for these individuals—by age 40, or 10 years earlier than the age at diagnosis of a family member. Early detection and removal of adenomatous polyps have made determining family history more difficult. Patients should be asked about removal of polyps in relatives, and those who have adenomatous polyps should be encouraged to tell their families.

A family history that contains many relatives with CRC, adenomatous polyps, or endometrial cancer, especially in more than one generation or with early-onset (age <50) suggests an autosomal dominant pattern of inheritance. Two relatively common, autosomal dominant, hereditary colorectal cancer syndromes account for about 3% to 5% of all CRC cases. Lynch syndrome, or hereditary nonpolyposis colon cancer syndrome (HNPCC), occurs in about 1 in 200 to 800 families and is underdiagnosed in primary care settings. Lynch syndrome is caused by mutations in mismatched repair genes and confers an approximately 80% lifetime risk of CRC. Often these cancers are right-sided and occur at an earlier age than sporadic CRC. Women with HNPCC have an increased risk for endometrial cancer; the incidence of other gastrointestinal and central nervous system cancers is also increased, but to a lesser degree. Evidence-based guidelines suggest that CRC screening with colonoscopy should begin in the 20s for affected individuals. Screening for endometrial cancer is also recommended, but there is less evidence of benefit. Evidence indicates that the disease burden could be reduced by screening tissue samples from all new CRC cases for molecular findings suggestive of Lynch syndrome. Family members of individuals testing positive then could be offered testing and enhanced surveillance if positive (EGAPP Working Group, 2009).

Familial adenomatous polyposis (FAP) is seen in about 1 in 8000 families, and affected individuals have a 100% lifetime risk of CRC. Management usually involves early screening (age 10-12) with sigmoidoscopy and early colectomy. Che-moprophylaxis with nonsteroidal anti-inflammatory drugs (NSAIDs) may also be of benefit.

Family physicians should recognize both FAP and HNPCC and ensure that genetic evaluation is offered to these families. If a specific mutation is identified, early screening of family members can be stopped for those testing negative. In the absence of a known mutation, all family members should be screened at an early age and the screening repeated at shorter intervals.

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