Cumulative evidence for relationships between multiple variants in the VTI1A and TCF7L2 genes and cancer incidence

Genetic studies have linked the VTI1A-TCF7L2 region with risk of multiple cancers. However, findings from these studies were generally inconclusive. We aimed to provide a synopsis of current understanding of associations between variants in the VTI1A-TCF7L2 region and cancer susceptibility. We conducted a comprehensive research synopsis and meta-analysis to evaluate associations between 17 variants in this region and risk of seven cancers using data from 32 eligible articles totaling 224,656 cancer cases and 324,845 controls. We graded cumulative evidence of significant associations using Venice criteria and false-positive report probability tests. We also conducted analyses to evaluate potential function of these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project. Eight variants showed a nominally significant association with risk of individual cancer (p < 0.05). Cumulative epidemiological evidence of an association was graded as strong for rs7903146 [odds ratio (OR) = 1.05, p = 4.13 × 10^-5 ] and rs7904519 (OR = 1.07, p = 2.02 × 10^-14 ) in breast cancer, rs11196172 (OR = 1.11, p = 2.22 × 10^-16 ), rs12241008 (OR = 1.13, p = 1.36 × 10^-10 ) and rs10506868 (OR = 1.10, p = 3.98 × 10^-9 ) in colorectal cancer, rs7086803 in lung cancer (OR = 1.30, p = 3.54 × 10^-18 ) and rs11196067 (OR = 1.18, p = 3.59 × 10^-13 ) in glioma, moderate for rs12255372 (OR = 1.12, p = 2.52 × 10^-4 ) in breast cancer and weak for rs7903146 (OR = 1.11, p = 0.007) in colorectal cancer. Data from ENCODE suggested that seven variants with strong evidence and other correlated variants might fall within putative functional regions. Collectively, our study provides summary evidence that common variants in the VTI1A and TCF7L2 genes are associated with risk of breast, colorectal, lung cancer and glioma and highlights the significant role of the VTI1A-TCF7L2 region in the pathogenesis of human cancers.