Tu1902 The Association of TGFβ Signalling Pathway Gene Polymorphisms With Colorectal Cancer Risk: A Meta-Analysis

Abstract

Introduction Background Approximately 35% of colorectal cancer risk is due to heritable factors. To date, a large fraction of this heritability remains unexplained. The TGFs signalling pathway has an increasingly implicated role in colorectal carcinogenesis, with highly penetrant-germline mutations of BMPR1A , SMAD4 and GREM1 causing known polyposis syndromes. We propose that common, low penetrance variation of TGFs signalling genes may account for much of the unexplained heritability of colorectal cancer, underlining the importance of this signalling pathway in the aetiology of colorectal cancer. Aim A meta-analysis of the association of TGFs signalling pathway gene single nucleotide polymorphisms (SNP) with low penetrance colorectal cancer risk. Methods A systematic literature search of Medline and Embase was performed. Data was extracted from eligible studies, according to pre-specified criteria. RevMan software, version 5.2, was used to generate pooled odds ratios (OR) to estimate the risk attributed to each variant. In addition to this, subgroup analyses for ethnicity, gender and tumour site were performed to investigate these as sources of heterogeneity. Results Between 9,854 and 27,641 cases were meta-analysed for each SNP. Of the 10 SNPs discovered in a review of the literature, 8 were significantly associated with an increased risk of colorectal cancer in this study. These SNPs were located within BMP4 , GREM1 , CDH1 , SMAD7 , RHPN2 and BMP2 , the largest effect was for rs10411210 within RHPN2 (OR=1.15; 95% CI 1.09- 1.22, I 2 50%). Subgroup analyses revealed gender as a possible source of heterogeneity, but no preferential associations for any of the SNPs with tumour site or ethnicity were detected. However determination of inconsistency between studies, i.e. I 2 of Conclusion Discussion: Whilst 8 out of 10 variants showed significant association, the estimates of risk were small with all OR Conclusions The results of this analysis underline the integral role of the TGFs signalling pathway in colorectal carcinogenesis. Knowledge of the function of tagged risk alleles is required to elucidate and accurately estimate the risk attributed to polymorphisms in this pathway. Keywords: colorectal cancer, TGFβ signalling, low penetrance Disclosure of Interest None Declared.