P-0235 Comparative Analysis of CpG Island Methylator Phenotype Between Different Groups of Colorectal Cancer According to the age of Onset

Abstract

ABSTRACT Introduction Colorectal Cancer (CRC) should no longer be considered one disease but rather a family of diseases, which is caused by genetic/epigenetic substrate. It is known that there are three main different carcinogenetic pathways for CRC. Extensive gene promoter methylation in CRC has been termed “CpG island methylator phenotype” (CIMP). This carcinogenetic pathway, also known as the “Methylator” phenotype, is the most recently identified and has a distinct clinical, pathologic, and molecular profile. The aim of our study was to characterize the clinical, pathological and familial features of CIMP-positive colorectal carcinomas within two different groups of onset, and consecutively identify possible differential features between both groups: early-onset and elderly CRC. Methods The methylation status of the promoter regions of the CIMP panel genes was carried out: CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1. CIMP-high was defined as the presence of ≥6/8 methylated promoters, CIMP-low as 1/8 to 5/8 methylated promoters and CIMP-0 as total absence (0/8) of methylated promoters. Statistical analyses were performed. We characterized the clinical, pathological and familial features of each group within each category of age, and compared each CIMP category between both groups of age. Only statistical significance differences are showed. Results Within early-onset CRC, 20% showed CIMP-High, 29% CIMP-low and 51% CIMP-0. Main differential features from CIMP-High tumours were: a higher proportion of tumours located at the right colon (67%), higher rate of low-grade of differentiation and mucinous tumours (29% and 57%, respectively), and a larger proportion of mixed polyps (adenomatous and hyperplastic) during follow-up (83%). Within elderly CRC, 24% showed CIMP-High, 26% CIMP-low, and 50% CIMP-0. Main features featuring CIMP-High tumours were: More female (67%), more tumours located at rectum (50%) and right colon (33%), more Microsatellite Instability (MSI) tumours (33%), with an absent of expression of Mlh1 (56%), and a higher proportion of BRAF mutations (28%). We compared each group of CIMP between both population groups (early-onset and elderly CRC). Comparing CIMP-High groups, early-onset against elderly, the first one showed more mucinous tumours (57%); more hiperplastic polyps (83% vs 29%); and more important familial component. For CIMP-low groups, early-onset showed more left-colon tumours (54% vs 16%); less proportion than within the elderly group of Multiple primary neoplasm and Synchronous or metachronous CRC; and finally there is a more important proportion of familial component. Finally, for CIMP-0 groups, early-onset CRC showed differential features: less right-colon tumours (9% vs 40%), they were earlier diagnosed, and with a higher familial component. Conclusion CIMP-High early-onset CRC showed different clinicopathological and familial features, compared with CIMP-High within elderly CRC. Methylation MLH1 and BRAF mutations are predominant in elderly CRC (sporadic cases with MSI). Whilst, some features of CIMP-High early onset overlap with Lynch syndrome characteristics. When we compared both populations, there are enough differences to suggest a different molecular basis in the development of the different groups of CIMP within early-onset CRC, compared with elderly CRC. This work was funded by the Spanish Fondo de Investigaciones Sanitarias (grant number FIS-PI10/0683).