Single Nucleotide Polymorphisms within Interferon Signaling Pathway Genes Are Associated with Colorectal Cancer Susceptibility and Survival

Shun Lu,Veronika Vymetalkova,Thomas Buchler,Bowang Cheng,Asta Försti,Pavel Vodicka,Kari Hemminki,Stefanie Huhn,Alessio Naccarati,Ludmila Vodickova,Barbara Pardini,Christophe Lamaze

doi:10.1371/journal.pone.0111061

Abstract

Interferon (IFN) signaling has been suggested to play an important role in colorectal carcinogenesis. Our study aimed to examine potentially functional genetic variants in interferon regulatory factor 3 (IRF3), IRF5, IRF7, type I and type II IFN and their receptor genes with respect to colorectal cancer (CRC) risk and clinical outcome. Altogether 74 single nucleotide polymorphisms (SNPs) were covered by the 34 SNPs genotyped in a hospital-based case-control study of 1327 CRC cases and 758 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall survival and event-free survival in a subgroup of 483 patients. Seven SNPs in IFNA1, IFNA13, IFNA21, IFNK, IFNAR1 and IFNGR1 were associated with CRC risk. After multiple testing correction, the associations with the SNPs rs2856968 (IFNAR1) and rs2234711 (IFNGR1) remained formally significant (P = 0.0015 and P<0.0001, respectively). Multivariable survival analyses showed that the SNP rs6475526 (IFNA7/IFNA14) was associated with overall survival of the patients (P = 0.041 and event-free survival among patients without distant metastasis at the time of diagnosis, P = 0.034). The hazard ratios (HRs) for rs6475526 remained statistically significant even after adjustment for age, gender, grade and stage (P = 0.029 and P = 0.036, respectively), suggesting that rs6475526 is an independent prognostic marker for CRC. Our data suggest that genetic variation in the IFN signaling pathway genes may play a role in the etiology and survival of CRC and further studies are warranted.

Highlights

Colorectal cancer (CRC) is an important contributor to cancer incidence and death, with more than 1.3 million new cases resulting in about 694,000 deaths in 2012 worldwide
74 single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) $10% in the CEU population were located within the regions of interest of the 20 genes IFNA (1, 2, 4, 5, 7, 8, 13, 16, 17, and 21), IFNB1, IFNK, IFNW1, interferon regulatory factor 3 (IRF3), IRF5, IRF7, IFNAR1, IFNAR2, IFNGR1 and IFNGR2
In this genetic association study, we investigated the associations between 34 SNPs capturing 74 potentially functional SNPs in the IFN-signaling system genes and CRC risk and clinical outcome

Summary

Introduction

Colorectal cancer (CRC) is an important contributor to cancer incidence and death, with more than 1.3 million new cases resulting in about 694,000 deaths in 2012 worldwide (http:// globocan.iarc.fr/Default.aspx). Not any GWAS, have reported SNPs in immune-related genes to be associated with CRC risk or prognosis [7,8,9,10]. IFNG, the only type II IFN, has been suggested to play a vital role in the disruption of the intestinal epithelial barrier function [14,15]. It has been identified as an important modulator of immune-related genes, such as toll-like receptor 3 (TLR3), the gene which showed association with CRC survival in our previous study [8]. All type I IFNs bind to a receptor composed of two subunits, IFNAR1 and IFNAR2, while the type II interferon IFNG binds to another dimeric receptor composed of IFNGR1 and IFNGR2

Methods

Results

Conclusion