Genetic variations in the CTLA-4 immune checkpoint pathway are associated with colon cancer risk, prognosis, and immune infiltration via regulation of IQCB1 expression.

The programmed cell death-1 (PD-1)/cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint pathways serve as targets of immunotherapy for colorectal cancer. However, the associations between genetic variations in these pathways and colorectal cancer risk, prognosis, and immune status remain unclear. The associations between single-nucleotide polymorphisms (SNPs) and colorectal cancer risk and survival were evaluated in a case-control study comprising 1150 cases and 1342 controls along with 287 cases with overall survival information. We found that individuals with the A allele of B7-2 rs2681416 in CTLA-4 immune checkpoint pathway had a significantly increased risk of colorectal cancer [odds ratio (OR) = 1.37, P = 3.17 × 10-4] than those with G allele under the dominant model, which had a predominant site-specific effect in colon cancer (OR = 1.55, P = 3.11 × 10-5). In addition, rs2681416 significantly decreased the overall survival time of patients with colon cancer [hazard ratio (HR) = 1.96, P = 1.10 × 10-2], but not of patients with rectal cancer (P = 0.271). Moreover, rs2681416 had an expression quantitative trait locus effect on the B7-2 flanking gene IQCB1 in colon tissues, which contributed to colon cancer risk by regulating genome organization and influenced the expression of IQCB1 in an allele-specific manner. IQCB1 expression was upregulated in colorectal cancer tissues compared with normal tissues, accounting for various critical carcinogenic states in colon cancer and promoting immune infiltration of Th17 cells in the tumor microenvironment. Our study highlights the important roles of genetic variations in immune checkpoint pathways and provides new insight into potential site-specific independent biomarkers for colorectal cancer susceptibility, prognosis, and tumor immune status.