Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer

Young J, Barker MA, Simms LA, Walsh MD, Biden KG, Buchanan D, Buttenshaw R, Whitehall VL, Arnold S, Jackson L, Kambara T, Spring KJ, Jenkins MA, Walker GJ, Hopper JL, Leggett BA, Jass JR (2005) Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 3:254-263

BACKGROUND AND AIMS: Recently, an alternative pathway of tumorigenesis has been identified in the colorectum associated with serrated precursor lesions, variable levels of microsatellite instability (MSI-V), and driven in part by activating mutations in the BRAF proto-oncogene (V599E). Somatic BRAF mutations in hereditary nonpolyposis colon cancer (HNPCC) are rarely observed. Here, we discuss their role in the development of other familial colorectal cancers (CRC). We studied non-FAP, non-HNPCC CRC families characterized by tumors that varied in their level of MSI between individual members. METHODS: A subset of tumors from a total of 55 collected (25 polyps and 30 cancers) from 43 individuals across 11 families underwent pathology review, examination for V599E using allele-specific polymerase chain reaction, and for methylation of the MINT31 CpG island. RESULTS: All MSI-V families met the current revised Bethesda Guidelines and 6 of 11 (55%) met the Amsterdam I criteria. V599E was observed in 12 of 19 (63%) polyps and 14 of 20 (70%) cancers (4 of 4 high MSI, 2 of 4 low MSI, and 8 of 12 stable MSI), a significant increase over HNPCC (0 of 15 or 0%), and unselected CRC (30 of 197 or 15.2%) ( P < .05).="" eight="" of="" the="" 10="" (80%)="" cancers="" that="" underwent="" analysis="" showed="" hypermethylation="" of="" mint31.="" crcs="" showed="" early="" age="" at="" onset="" and="" were="" more="" likely="" to="" show="" a="" serrated="" architecture="" than="" unselected="" crcs="" (="" p="">< .05).="" conclusion:="" these="" data="" provide="" evidence="" that="" the="" families="" described="" here="" represent="" a="" syndrome="" of="" familial="" crc="" that="" is="" distinct="" from="" hnpcc.="" high="" levels="" of="" braf="" mutation="" and="" mint31="" hypermethylation="" suggest="" an="" origin="" in="" the="" serrated="" pathway="" of="" crc="">