Abstract LB-15: Oncogenic BRAF mutation, IGFBP7 silencing and evasion of senescence in colorectal tumorigenesis

Abstract

Abstract Serrated polyps are now recognized as the precursor lesion from which sporadic BRAF (V600E) mutant/CIMP-H colorectal cancers (CRC) develop, but it appears likely BRAF mutation alone is not enough to drive progression to carcinoma. CIMP is generally localized to the proximal colon and may cause the epigenetic silencing of key genes such as IGFBP7 that may act in concert with BRAF mutation to promote neoplasia. We are conducting a detailed molecular analysis of the mechanism of serrated neoplasia involving IGFBP7 and evasion of oncogene-induced senescence (OIS). Normally senescence functions as a defense mechanism against tumorigenesis in precursor lesions. We have analysed 44 CRCs and 217 colorectal polyps including 45 advanced serrated polyps (sessile serrated adenomas, serrated adenomas and mixed polyps) and 109 simple serrated polyps (goblet cell rich hyperplastic polyps and microvesicular hyperplastic polyps) for BRAF, K-ras and CIMP relative to clinicopathologic variables. In addition a MethyLight assay was developed to determine IGFBP7 methylation patterns in serrated polyps and cancers. For serrated polyps, both BRAF mutation (75.5%) and CIMP (46.6%) was most frequent in advanced serrated polyps (ASPs). Overall the frequency of CIMP was significantly associated with proximal location (P<0.0001) and larger size (P<0.005). When serrated polyps were analyzed separately, histological type and location showed strong associations, with CIMP frequency differing significantly in proximal vs distal BRAF mutant ASPs and GC/MV-HPs. We find that BRAF mutation is highly associated with both SSAs and MV-HPs throughout the colorectum, but only in proximal SSAs is CIMP highly associated with BRAF mutation (70.8%). For CRCs we found IGFBP7 methylation frequently associated with CIMP and BRAF mutation (87%). For serrated polyps, IGFBP7 methylation was significantly associated with ASPs (P<0.0002), larger size (P<0.0002) and proximal location (P<0.0004). In advanced serrated polyps, which harbour both BRAF mutation and exhibit CIMP, methylation of IGFBP7 was observed 65% of cases. We are currently determining p53 expression levels, Ki67 and the senescence markers p19ARF and Dec1 in different serrated polyp types. This investigation will provide evidence for the involvement of IGFBP7 loss, by DNA hypermethylation, in the evasion of senescence and resulting in the progression of BRAF mutant/CIMP-H carcinoma of the colon. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-15.