Abstract 1673: BRAF mutation is associated with large, proximal sessile serrated polyps, but not with adenomas

Abstract

Abstract Background: Different colorectal cancer (CRC) pathways result in tumors with distinct phenotypic and molecular signatures. The adenoma-carcinoma pathway involves conventional adenoma precursors, resulting in tumors that tend to exhibit chromosomal instability but lack microsatellite instability. Less is established about the origin of microsatellite unstable CRC. This sub-set of tumors includes some tumors with aberrant methylation, which often exhibit activating mutations in the BRAF oncogene, and are commonly found in the proximal colon. Objective: We aimed to compare the prevalence of BRAF-mutation between distinct colorectal polyp types. Methods: We conducted a case-case comparison of BRAF-mutation status in polyp tissue DNA from participants aged 24-79 in a colonoscopy-based study, who were diagnosed with colorectal adenomas or hyperplastic polyps (HPs). During colonoscopy, polyps were biopsied, fixed in paraffin, and H&E slides prepared. All participants underwent a standard pathology review to confirm the diagnosis and determine the percent of lesional tissue in the block. Polyps classified as tubular adenomas or tubulovillous adenomas were considered conventional adenomas; those classified as HPs, sessile serrated polyps, or traditional serrated adenomas were considered serrated polyps. Medical records were abstracted to ascertain polyp location and size; tissue blocks from polyps at least 3 mm in diameter and containing at least 80% lesional tissue were selected for BRAF analyses. BRAF-mutation status was determined using 2 assays specific for the V600E mutation. A validated TaqMan assay was run on all samples, and a fluorescent allele-specific PCR assay was run on a subset for quality control. Of the 1044 polyp DNA samples tested, 880 (84%) were successfully assayed. Results: Of 529 conventional adenomas, including 129 tubulovillous adenomas, only 2 (0.4%) had V600E BRAF-mutations. Among serrated polyps, 176 of 351 (50%) were BRAF-mutation positive. Of these, sessile serrated polyps had the highest prevalence of a BRAF-mutation: 74 of 120 (62%), followed by traditional serrated adenomas: 5 of 11 (45%), and HPs: 97 of 220 (44%). Polyp location and size were also associated with a BRAF-mutation. For serrated polyps, 45 of 98 (46%) rectal, 39 of 95 (41%) distal colon, and 92 of 156 (59%) proximal colon polyps were BRAF-mutated. Serrated polyps ≤ 10 mm had a higher prevalence of BRAF-mutation than those < 10 mm (69% vs. 48% with BRAF-mutation, respectively). Discussion: Our results suggest that BRAF-mutation is commonly found in serrated polyps, but rarely occurs in conventional adenomas. Among serrated polyps, the prevalence of BRAF-mutation was highest in polyps that were proximally located, β10 mm, and with sessile serrated histology. These findings support the thesis that serrated polyps may be important precursors for the subset of CRC exhibiting BRAF-mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1673. doi:1538-7445.AM2012-1673