Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominant cancer syndrome that confers an elevated risk of early-onset colorectal cancer (CRC) and increased lifetime risk for other cancers of the endometrium, stomach, small intestine, hepatobiliary system, kidney, ureter, and ovary. Lynch syndrome accounts for up to 3% of all CRC, making it the most common hereditary colorectal cancer syndrome. Germline mutations in methyl-directed mismatch repair (MMR) genes give rise to microsatellite instability (MSI) in tumor DNA. Lynch syndrome is most frequently caused by pathogrenic variants in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Germline mutations in MLH1 and MSH2 account for approximately 90% of detected mutations in families with Lynch syndrome. Pathogenic vatiants in MSH6 have been reported in approximately 7-10% of families with Lynch syndrome. Pathogenic variants in PMS2 account for fewer than 5% of mutations in families with Lynch syndrome. This unit presents a comprehensive molecular genetic testing strategy for Lynch syndrome including MSI analysis, next generation sequencing (NGS)-based targeted sequence analysis, PCR-based Sanger sequencing and microarray-based comparative genomic hybridization (array-CGH). © 2017 by John Wiley & Sons, Inc.