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

Abstract

<div><p>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 (<i>IRF3</i>), <i>IRF5</i>, <i>IRF7</i>, type I and type II <i>IFN</i> 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 <i>IFNA1</i>, <i>IFNA13</i>, <i>IFNA21</i>, <i>IFNK</i>, <i>IFNAR1</i> and <i>IFNGR1</i> were associated with CRC risk. After multiple testing correction, the associations with the SNPs rs2856968 (<i>IFNAR1</i>) and rs2234711 (<i>IFNGR1</i>) remained formally significant (<i>P</i> = 0.0015 and <i>P</i><0.0001, respectively). Multivariable survival analyses showed that the SNP rs6475526 (<i>IFNA7/IFNA14</i>) was associated with overall survival of the patients (<i>P</i> = 0.041 and event-free survival among patients without distant metastasis at the time of diagnosis, <i>P</i> = 0.034). The hazard ratios (HRs) for rs6475526 remained statistically significant even after adjustment for age, gender, grade and stage (<i>P</i> = 0.029 and <i>P</i> = 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.</p></div