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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.LB-15-LB-15
• Main Authors: Spring, Kevin J., Miranda, Mariska, Fernando, Winnie, Togashi, Kazutomo, Young, Graeme P., Leggett, Barbara A.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-LB-15

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