Somatic BRAF mutations in colorectal cancer andmicrosatellite instability phenotypes.

B197 Background : Somatic mutations in BRAF are characteristic of microsatellite instable (MSI-H) colorectal cancers, including the subset of cancers recognized as the CpG Island Methylator Phenotype (CIMP). Estimates of the population prevalence and epidemiologic characteristics of cancers harboring BRAF mutations are not yet fully described. Methods : Incident, population-based cases of colorectal cancer from the Molecular Epidemiology of Colorectal Cancer (MECC) study in northern Israel were examined for microsatellite instability using DNA derived from microdissected sections of paraffin-embedded tumor blocks. BRAF mutations were assessed by sequencing of exon 15 from the same tumor DNA used for MSI analyses. Ongoing methylation analyses to identify CIMP colorectal cancers using a newly validated panel of methylation markers are performed on a Pyrosequencing platform. Results : The microsatellite instable-high (MSI-H) phenotype was observed in 11.8% of 1489 colorectal adenocarcinomas with available blocks. BRAF somatic mutations were identified in 5.7% of the 664 cancers with complete analysis of MSI and BRAF . Somatic BRAF mutation was strongly associated with MSI, with BRAF V600E mutations identified in identified in 26.5% of MSI-H tumors and 2.1% of stable/microsatellite low tumors (OR=16.6, 95% CI=8.0 - 34.4). Smoking was not strongly associated with the presence of a BRAF mutation (OR=0.76, 95% CI=0.37 - 1.54) among all tumors. Among those tumors that were MSI-H, there was a suggestion of an inverse association between smoking and BRAF mutation, although this was not statistically significant (OR=0.47, 95% CI=0.18 - 1.24). Ongoing methylation analyses will permit further characterization of MSI-H tumors arising within the context of CIMP and a corresponding BRAF mutation compared to those with germline mutations of a mismatch repair gene. Conclusion : Somatic BRAF mutation in colorectal cancer is strongly associated with MSI-H tumors, suggesting that there are multiple MSI-H phenotypes that are likely to have distinct epidemiologic features.