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Interferons (IFNs) are proteins involved in many functions including antiviral and antimicrobial response, apoptosis, cell cycle control and mediating other cytokines. IFN gamma (IFNG) is a proinflammatory cytokine that modulates many immune-related genes. In this study we examine genetic variation inIFNG,IFNGR1,IFNGR2and interferon regulatory factors (IRFs) to determine associations with colon and rectal cancer and survival after diagnosis. We include data from two population-based incident studies of colon cancer (1555 cases and 1956 controls) and rectal cancer (754 cases and 959 controls). Five tagSNPs inIFNG,IRF2andIRF3were associated with colon cancer and eight tagSNPs inIFNGR1,IFNGR2,IRF2,IRF4,IRF6andIRF8were associated with rectal cancer.IRF3rs2304204 was associated with the strongest direct association andIRF23775554 with the strongest inverse association for colon cancer [odds ratios (ORs) 1.43, 95% confidence interval (CI) 1.12–1.82 for recessive model and 0.52, 95% CI 0.28–0.97 for unrestricted model]. For rectal cancer,IFNGR1rs3799488 was directly associated with risk (OR 2.30, 95% CI 1.04–5.09 for recessive model), whereasIRF6rs861020 was inversely associated with risk (OR 0.57, 95% CI 0.34–0.95). Several single-nucleotide polymorphisms interacted significant with bothNF-κB1andIL6and with aspirin/non-steroidal anti-inflammatory drugs and cigarette smoking. Using a summary score to estimate mutational load, we observed a hazard rate ratio (HRR) close to 5.00 (95% CI 2.73–8.99) for both colon and rectal (HRR 4.83, 95% CI 2.34–10.05) cancer for those in the category having the most at-risk genotypes. These data suggest the importance of IFN-signaling pathway on colon and rectal cancer risk and survival after diagnosis.

Interferon-signaling pathway: associations with colon and rectal cancer risk and subsequent survival