Molecular tumor testing for Lynch syndrome in patients with colorectal cancer

Lynch syndrome (LS) is the most common hereditary colon cancer syndrome, and accounts for 2% to 3% of all colorectal cancers. These tumors are caused by germline mutations of DNA mismatch repair genes, which result in microsatellite instability. Colonic and extracolonic malignancies can occur at a young age, and are often diagnosed at a late stage because of underrecognition of the syndrome. Identifying individuals with LS before the development of these malignancies decreases mortality because of frequent screening and surveillance of colonic and extracolonic cancers. Moreover, family members of these individuals can be tested and begin screening at a young age if appropriate. Classically, Amsterdam criteria and Bethesda guidelines have been used to identify at-risk individuals; however, these tools miss a significant number of cases. As the molecular basis for LS has been clarified, more sophisticated strategies have emerged. Testing all colorectal cancers for loss of mismatch repair proteins, known as universal screening, is a strategy used to identify individuals at risk for LS. This approach has been shown to be more sensitive than previous methods that rely on family history. Implementation of universal tumor testing necessitates a systematic approach to positive results in order to have maximal effect, and could prove to be the most cost-effective approach to reducing cancer mortality in patients with LS.