BRAF Mutations Exclude Lynch Syndrome

Hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) is caused by mismatch-repair gene mutations, and HNPCC tumors demonstrate microsatellite instability (MSI). HNPCC accounts for 1% to 5% of colorectal cancers in the U.S., but approximately 15% of all colorectal cancers display MSI, which can complicate cancer typing. Non-HNPCC tumors with MSI are caused by hypermethylation of the MLH1 gene. This acquired epigenetic inactivation of MLH1 is associated with diffuse hypermethylation and, typically, with mutations in the BRAF gene. In fact, the germline mismatch-repair gene mutations in HNPCC and BRAF mutations are mutually exclusive. Could testing MSI-positive tumors for BRAF mutations attenuate germline testing for mismatch-repa…