P1576Association of colorectal cancer with genetic and epigenetic variation in PEAR1 - a population-based cohort study

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Abstract Background Platelet Endothelial Aggregation Receptor 1 (PEAR1) modulates angiogenesis and platelet contact-induced activation, which play a role in the pathogenesis of colorectal cancer. Purpose To study the association of colorectal cancer with genetic and epigenetic variation in PEAR1. Methods Among 2532 randomly recruited participants enrolled in the family-based Flemish Study on Environment, Genes and Health Outcomes (51.2% women; mean age 44.8 years), we recorded the incidence of colorectal cancer and genotyped SNP rs12566888 located in intron 1 of the PEAR1 gene. In 929 participants, we also measured the methylation at 16 CpG sites in the PEAR1 promoter. In multivariable-adjusted analyses, we contrasted the risk of colorectal cancer in minor-allele (T) carriers vs. major allele (GG) homozygotes. We applied partial least square discriminant analysis (PLS-DA) to identify methylation sites associated with colorectal cancer. Results Over a median follow-up of 18.1 years, 49 patients developed colorectal cancer. While accounting for clustering within families and adjusting for sex, age, body mass index, the total-to-HDL cholesterol ratio, serum creatinine, plasma glucose, smoking and drinking, use of antiplatelet and nonsteroidal anti-inflammatory drug, the hazard ratio contrasting minor allele carriers vs. major allele homozygotes was 2.17 (95% confidence interval, 1.18–3.99; P=0.013). Bootstrapped analyses, from which we randomly excluded from two to nine cancer cases, provided confirmatory results. PLS-DA identified two methylation sites in the PEAR1 promoter associated with higher colorectal cancer risk and two with lower risk. In-silico analysis suggested that methylation of the PEAR1 promoter at these four sites affects binding of the transcription factors p53, PAX5, and E2F-1, thereby modulating gene expression. Potential pathways Conclusions Our findings suggest that genetic and epigenetic variation in PEAR1 modulates the risk of colorectal cancer in white Flemish. Acknowledgement/Funding The European Union, the European Research Council, the European Research Area Net for Cardiovascular Diseases, and the Research Foundation Flanders.