Targeted Next-Generation Sequencing for Hereditary Cancer Syndromes : A Focus on Lynch Syndrome and Associated Endometrial Cancer

Lynch syndrome is a hereditary cancer syndrome that results from germline mutations in one of the DNA mismatch repair genes, leading to an increased lifetime risk of cancer. Colorectal cancer is most commonly identified with Lynch syndrome; however, women with Lynch syndrome have an increased risk of developing endometrial cancer (up to 60%), which is the sentinel diagnosis in approximately one-half of the cases. Current screening algorithms are developed on family history and laboratory-based tests, including immunohistochemistry for mismatch repair proteins and microsatellite instability testing. Next-generation sequencing assays are rapidly being incorporated into clinical laboratory practices and have diagnostic applications for hereditary cancer syndromes. Important challenges of next-generation sequencing include interpreting incidental and uncertain findings, counseling before and after testing, and informed consent of patients. Here, with the use of Lynch syndrome in endometrial cancer as a model, some of the applications and intricacies of next-generation sequencing testing for hereditary cancer syndromes are reviewed.