Abstract 5539: A predominant serrated pathway in hyperplastic polyposis syndrome generates microsatellite-stable and -unstable colorectal cancers

Abstract

Abstract Background and aims: Hyperplastic polyposis syndrome (HPS) is characterized by the presence of multiple colorectal serrated polyps and is associated with an increased colorectal cancer (CRC) risk. The mixture of distinct precursor lesion types and malignancies provides a unique model to study the canonical pathway and a proposed serrated CRC-pathway in humans. Methods: To establish which CRC-pathways play a role in HPS and particularly to obtain new support for the serrated CRC pathway, we analyzed the molecular characteristics of polyps (n=84) and CRCs (n=19) in 17 HPS patients as compared to control groups of various sporadic polyps(n=59) and sporadic microsatellite-stable CRCs(n=16). Results: In both HPS and sporadic polyps, APC mutations were exclusively identified in adenomas whereas BRAF mutations were confined to serrated polyps. Six of 19(32%) HPS CRCs were identified within a serrated polyp. Mutation analysis performed in both the CRC and the serrated component of these lesions showed identical BRAF mutations. One HPS CRC was located within an adenoma, both components harboring an identical APC mutation. Overall, 10/19(53%) HPS CRCs carried a BRAF mutation, compared to none in control group CRCs (p=0.001). Six of the BRAF-mutated HPS CRCs were microsatellite-unstable (MSI-high) due to MLH1 methylation. Conclusion: Our findings provide novel supporting evidence for the existence of a serrated CRC pathway which predominates over the classical Wnt pathway of carcinogenesis in HPS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5539. doi:10.1158/1538-7445.AM2011-5539