Genetic variants in hypoxia-inducible factor pathway are associated with colorectal cancer risk and immune infiltration

Hypoxia-inducible factor (HIF) pathway genes influence tumorigenesis and immune status. However, the associations between genetic variants in hypoxia-related genes and colorectal cancer risk and the immune status of hypoxia-associated genes in colorectal cancer have not been systematically characterized. The associations between genetic variants and colorectal cancer risk were evaluated in Chinese, Japanese and European populations using logistic regression analysis. The relationships between target genes and tumour immune infiltration were predicted by Tumour Immune Estimation Resource (TIMER). We found that rs34533650 in EPAS1 was associated with colorectal cancer risk (OR = 1.43, 95% CI = 1.20-1.70, P(FDR) = 8.35 x 10-4), and this finding was validated in two independent populations (Japanese: OR = 1.07, 95% CI = 1.01-1.15, p = 3.38 x 10-2; European: OR = 1.11, 95% CI = 1.03-1.19, p = 6.04 x 10-3). EPAS1-associated genes were enriched in immune-related pathways. In addition, we found that EPAS1 copy number variation (CNV) was associated with the degree of infiltration of immune cells and observed correlations between EPAS1 expression and immune cell infiltration levels in colorectal cancer. These results highlight that genetic variants of hypoxia-related genes play roles in colorectal cancer risk and provide new insight that EPAS1 might be a promising predictor of colorectal cancer susceptibility and immune status.