Risk Assessment, Genetic Testing, and Management of Lynch Syndrome

Of the estimated 150,000 colorectal cancer (CRC) cases diagnosed annually, approximately 30% have a familial basis and 3% to 5% are from high-penetrance inherited cancer syndromes. Lynch syndrome, or hereditary nonpolyposis colorectal cancer, caused by inherited germline mutations in mismatch repair (MMR) genes, is the most commonly inherited CRC syndrome. It is characterized by young-onset CRC and an increased risk for extracolonic tumors, including gynecologic, urinary tract, and other gastrointestinal cancers. Commercial testing is available for mutations in the MMR genes, but testing all patients with CRC would be economically prohibitive. Therefore, a comprehensive evaluation of a multigenerational family cancer history is essential for the identification of at-risk individuals. The presence of tumors diagnosed at a young age, multiple first- and second-degree relatives with cancer, or 2 or more primary cancers may be indicative of an inherited cancer syndrome and these individuals should undergo genetic evaluation. Genetic test results, when conclusive, can guide management for patients and their families. However, indeterminate test results may provide false reassurance to patients who should be managed as being at higher-than-average risk. Online risk assessment tools and commercial genetic testing offer the potential to identify a greater number of at-risk individuals at an earlier age. However, for these measures to improve outcomes, patients must receive screening recommendations and counseling appropriate for their cancer risk.