A prospective study of BRAF and K-ras mutations in colorectal polyps: location, histologic subtype and clinical relevance

388 Colorectal cancer (CRC) is a leading cause of cancer mortality and is considered a heterogenous disease. The majority of CRCs arise sporadically through the accumulation of genetic alterations and clonal expansion. Approximately 15% of sporadic CRC exhibit high-level microsatellite instability (MSI-H) and are frequently associated with the CpG island methylation phenotype (CIMP). The initiation and progression of sporadic MSI-H cancers is less well understood and may evolve from hyperplastic polyps (HPs). Previously, hyperplastic polyps as opposed to adenomas were considered to have little or no malignant potential, but this view is being increasingly challenged. It has been proposed that a subset of HPs predispose to sporadic MSI-H cancers and progress through an alternate serrated neoplastic pathway involving oncogenic BRAF (V600E) mutation. Recently oncogenic BRAF mutations have been identified in hyperplastic polyps, serrated adenomas (SA) and carcinomas of the colorectum. Both BRAF and K-ras are involved in the MAP kinase signalling pathway, which influences cell differentiation, proliferation, survival and apoptosis. Activation of this pathway may be an early event in the development of sporadic MSI-H cancers from a specific subset of HPs. In this study we investigated prevalence, location, size, and mutation of BRAF and K-ras in all colorectal polyps obtained from an unselected series of colonoscopies. Two hundred patients were recruited for this study and of these 151 had polyps. All polyps were removed and 99% were retrieved for histology and further analysis. 449 polyps from 146 patients were classified by a single pathologist and further analysed for BRAF and K-ras mutations. Polyps were classified as HPs either of goblet cell (GC) or microvesicular (MV) sub-type, serrated adenomas (SAs), sessile serrated adenomas (SSAs), mixed polyps (MPs), tubular adenomas (TAs) and tubulovillous adenomas (TVAs). Polyps were screened for A1796 activating BRAF mutations (V600E) and K-ras codon 12 and 13 mutations using both an allele-specific real-time PCR assay and Sequenom MassARRAY assay. Of these 32% were HPs (consisting of 19% GC and 13% MV sub-type), 1% SAs, 1.5% MPs, 12% SSAs, 50 % TAs and 4% TVAs. The majority of GC- and MV- HPs were distal in location compared with SSAs, SAs and MPs which were mainly proximally located. In SSAs, SAs and MPs BRAF mutations were more highly represented (79%), whereas K-ras mutations were uncommoon (8%). Conversely, BRAF mutation was extremely rare in TAs and TVAs (0.6%). In conclusion the high prevalence of BRAF mutation in proximal serrated polyps (SSAs, SAs and MPs) provides further support for the serrated neoplastic pathway in the development of sporadic MSI-H colorectal cancer.

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