P-0298 - Study of Association of Smad7 Single Nucleotide Polymorphisms with Risk and Prognosis of Colorectal Cancer in a Portuguese Population

Abstract

Background: The smads are intracellular proteins critical to the transmission of signals from the transforming growth factor-β (TGF- β) pathway to the nucleus. SMAD7 is a potent antagonist of TGF- β signalling pathways and genome-wide association studies (GWAS) linked three single nucleotide polymorphisms (SNPs) in SMAD7 gene (rs4464148, rs4939827 and rs12953717) to a modest increase in the susceptibility to colorectal cancer (CRC) development. Some studies even hypothesized that SMAD7 correlates with the development of metastasis and prognosis of CRC. The main aim of this study is to investigate the association between these three SNPs and the risk of CRC in an independent Portuguese population. The authors also accessed the eventual impact on the prognosis of this disease. Methods: This was a population-based case-control retrospective study that included 202 patients diagnosed with CRC and 197 healthy controls, from northern Portugal. The DNA (obtained from nucleated blood cells) was genotyped for a panel of 3 SNPs (rs4464148, rs4939827 and rs12953717) using a Sequenom® MassARRAY platform. We performed a multivariate logistic regression analysis (which included age and sex as covariates) to calculate Odds Ratio (OR) and 95% confidence intervals (CI) of association between SMAD7 SNPs and risk of CRC. ACox regression model was used to calculate Hazard ratios (HR), adjusted to age and sex, in the survival analysis. Results: The median age of patients at diagnosis was 66 years old and the majority of the tumors were located in the colon (61%). The median age of controls was 50 years old. Median time offollow up was 40 months. We replicated the association of the SNP rs4939827 with the risk of CRC. Compared with the TT genotype, the carriers of the CT genotype had an adjusted OR of 2.38 (95% CI: 1.03-5.46; p = .04). The analysis of the SNP rs12953717 revealed a strong tendency for association of the genotype TT with increased risk of CRC (OR = 3.87, 95% CI: 0.99-15.2; p = .052). The rs4464148 did not show any association with cancer risk. None of the SNPs depicted an association with patient’s survival. Conclusion: Replications offindings in GWAS are important to secure that the evidence of association with disease risk is robust. This is the first study that analyzes the SMAD7 SNPs in the Portuguese population. We found an association between the genotype CT in the SNP rs4939827 and increased risk of CRC. The other two SNPs studied did not correlate with CRC risk in our population. Overall survival of the patients also did not relate to the variants of these three SMAD7 polymorphisms.