Abstract
Abstract The risk of colorectal cancer (CRC) is determined by the interplay of genetic and environmental factors. The aim of this study was to identify the association between polymorphisms in cell-cycle related genes and risk of colorectal cancer, and to evaluate the interaction with non-steroidal anti-inflammatory drug (NSAID) use. Patients with incident CRC were recruited in the framework of DACHS, a German population based case-control study. Altogether, 1756 cases and 1781 controls were genotyped for 223 candidate or tagging SNPs in 30 cell-cycle related genes using the Illumina GoldenGate Assay. The associations between polymorphisms and the risk of colorectal cancer were assessed with multivariate logistic regression. Effect modification by NSAIDs (use >1/month for >1 year) was tested by using a multiplicative interaction term. Haplotype analysis was performed using the haplo.stats R package. None of the studied SNPs were significantly associated with CRC after multiple test correction. NSAID use lowered the risk of colorectal cancer with an odds ratio (OR) of 0.59 (Confidence interval, CI: 0.51-0.69, p = 9.58*10-11). Several polymorphisms in and near cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 2 (CDK2) showed interaction with NSAID use. However, only one signal remained significant after FDR correction; the homozygous wild genotype (GG) of rs2069408 neutralizes the protective effect of NSAID use (interaction p<0.001, FDR q = 0.018). The effect of NSAID use on CRC risk according the rs2069408 genotypes were the following (OR, 95%CI): 0.82 (0.65-1.02) for GG, 0.51 (0.42-0.61) for GA and 0.31 (0.22-0.45) for AA genotypes. Although non-significant after multiple test correction, interactions with NSAID use was observed at the rs4134950 polymorphism of the E2F3 gene (interaction p = 0.003, FDR q = 0.152) and at rs17187428 (interaction p = 0.004, FDR q = 0.164) and rs773108 (interaction p = 0.005, FDR q = 0.166) in MYC. The haplotype analysis revealed six haplotype blocks in and near the genes E2F3, CDK2, CDK1, CDK6 and MYC that showed significant interaction with NSAID use regarding the risk of colorectal cancer. A possible mechanism of the interaction between NSAIDs and cell-cycle genes could be mediated via the cell-cycle related effects of MYC, the expression of which is regulated by the Wnt/ß-catenin pathway. This pathway plays a central role in colorectal cancer and was previously found to be inhibited by NSAIDs. The analyses of additional SNPs are ongoing to better understand the mechanism of the interaction between NSAID use and cell-cycle related genes. Citation Format: Reka Toth, Yesilda Balavarca, Dominique Scherer, Nina Habermann, Katharina Buck, Akke Botma, Elisabeth J. Kap, Axel Benner, Alexis Ulrich, Michael Hoffmeister, Hermann Brenner, Barbara Burwinkel, Jenny Chang-Claude, Cornelia M. Ulrich. Polymorphisms in cell-cycle related genes modify the effect of NSAIDs on the risk of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4590. doi:10.1158/1538-7445.AM2015-4590
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