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

Abstract

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 in IFNG, IFNGR1, IFNGR2 and 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 in IFNG, IRF2 and IRF3 were associated with colon cancer and eight tagSNPs in IFNGR1, IFNGR2, IRF2, IRF4, IRF6 and IRF8 were associated with rectal cancer. IRF3 rs2304204 was associated with the strongest direct association and IRF2 3775554 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, IFNGR1 rs3799488 was directly associated with risk (OR 2.30, 95% CI 1.04-5.09 for recessive model), whereas IRF6 rs861020 was inversely associated with risk (OR 0.57, 95% CI 0.34-0.95). Several single-nucleotide polymorphisms interacted significant with both NF-κB1 and IL6 and 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.

Cytokines of the Immune System

“…IRF3 rs2304204 was associated with the strongest direct association and IRF2 rs3775554 with the strongest (protective) inverse association for colon cancer. 21 The IFNGR1 -56C/T gene polymorphism (rs17175350) is associated with increased risk of early gastric carcinoma. 22 Polymorphisms in IFNGR2 (Ex7-128 C>T) (and also TNFA -308 A>G) may increase the risk of gastric cancer.…”

Role of cytokines and Jak3/Stat3 signaling in the 1,2-dimethylhydrazine dihydrochloride-induced rat model of colon carcinogenesis

“…IFNg is the only type II IFN that can act as a proinflammatory cytokine and its association with the pathogenesis of several chronic inflammatory conditions has been well reported in various studies (Wheelock, 1965;Heremans and Billiau, 1989). IFNs are involved in many functions such as antiviral and antimicrobial responses, apoptosis, cell cycle control, and as mediators of other cytokines (Slattery et al, 2011). IL-4 has been shown to be an anti-inflammatory cytokine involved in various immune responses with pleiotropic functions (Nelms et al, 1999).…”

Colorectal Cancer Immunotherapy: Current State and Prospects (Review)

“…Initially high expectations in colon cancer treatment were related to the use of interferons, since they have a direct and indirect (mediated via immunocompetent cells) antitumor effect: suppression of tumor cell proliferation, induction of their apoptosis, increased of МНС class I molecules expression, stimulation of NK and cytotoxic cells, anti-angiogenic effect [75]. However, longterm clinical trials of interferon therapy capabilities of this oncopathology showed ambiguous results.…”

“…On the one hand, there has been demonstrated the efficacy of adding IFN-α chemotherapy on colorectal carcinoma cell lines [73,74]; furthermore, there are evidences in favor of the fact that polymorphism in reviews interferon signal pathway genes is associated with high susceptibility to colon cancer [76,77] The studies on using IL-2 as a part of a combined therapy in colorectal cancer appeared to be more successful. It causes apoptosis of tumor cells, stimulation of Т, В and NK lymphocytes and also is able to produce anti-angiogenic effect [75]. The results of recent clinical trials have shown that granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-2 (GOLFIG mode) supplemented to conventional chemotherapy results in an increase of total and progressive-free survival in colon cancer patients [82,83].…”