Abstract
Lynch syndrome is a hereditary cancer syndrome that accounts for most inherited forms of endometrial and colorectal cancers and also increases the lifetime risk of developing many other types of malignancies including ovarian cancer. Lynch syndrome is caused by autosomal-dominant mutations in one of four mismatch-repair (MMR) genes responsible for recognizing and repairing certain forms of DNA damage. Patients whose cells lack this repair function are predisposed to develop early-onset and multiple tumors. Therefore, it is imperative that once a mutation in an MMR gene is detected in a patient, the family should undergo genetic counseling and cascade testing to identify carriers who are at high risk. Current guidelines recommend universal tumor screening for Lynch syndrome in all patients with endometrial and colorectal cancers at the time of diagnosis. Because patients with Lynch syndrome and certain other MMR-deficient tumors have high microsatellite instability (MSI-high), checkpoint inhibitors offer a new approach to target the increased level of tumor neoantigens resulting from the mutational burden across a wide range of cancers. One such checkpoint inhibitor, pembrolizumab (Keytruda), was recently approved for patients with advanced solid tumors that are MSI-high or MMR-deficient whose disease has progressed after prior treatments and for those with colorectal cancer that has progressed after chemotherapy.
