Background Approximately 35% of colorectal cancer risk is due to heritable factors. To date, a large fraction of this heritability remains unexplained. The TGFß 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 TGFß 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 TGFß 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, I2 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. I2 of <50% for 8 of 10 SNPs, indicated that overall study heterogeneity was not a common source of bias.
Conclusion Discussion: Whilst 8 out of 10 variants showed significant association, the estimates of risk were small with all OR <1.15. This may result from suboptimal methods of estimating risk, as well as unknown disease heterogeneity. This process is constrained by a lack of knowledge of the true risk alleles tagged by the SNPs studied.
Conclusions The results of this analysis underline the integral role of the TGFß 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.
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