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

<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

Associations between candidate SNPs and colorectal cancer susceptibility.

1<p>Number of cases may differ due to missing data.</p>2<p>Two-sided X² test for genotype distribution between the cases and controls, adjusted for age and gender.</p><p>No., number of subjects; OR, odds ratio; CI, confidence interval. Bold numbers indicate a statistical significance at 5% level.</p><p>Bold numbers in Italics indicate a statistical significance at 5% level after adjustment for multiple comparisons.</p><p>Associations between candidate SNPs and colorectal cancer susceptibility.</p

Characteristics of the 483 newly diagnosed Czech colorectal cancer patients.

<p>No., number of patients; T, size or direct extent of the primary tumor; N, degree of spread to regional lymph nodes; M, presence of metastasis.</p><p>Characteristics of the 483 newly diagnosed Czech colorectal cancer patients.</p

Association of rs7047687, rs6745526 and rs11770589 with overall and event-free survival of newly diagnosed colorectal cancer patients.

1<p>Overall survival was calculated for all patients diagnosed between 2003 and 2010 (n = 483).</p>2<p>Event-free survival was calculated for patients diagnosed between 2003 and 2010, who did not have distant metastasis at the time of diagnosis</p><p>(n = 325).</p>3<p>Number of cases may differ due to missing data.</p><p>No., number of patients; OR, odds ratio; CI, confidence interval; M = 0, no distant metastasis present Bold numbers indicate a statistical significance at 5% level.</p><p>Association of rs7047687, rs6745526 and rs11770589 with overall and event-free survival of newly diagnosed colorectal cancer patients.</p

Polymorphisms evaluated in this study.

1<p>Minor allele frequency (MAF) based on Utah residents with Northern and Western European ancestry from the CEPH collection in the HapMap project.</p>2<p>Pairwise linkage disequilibrium (r²) was calculated for the SNPs with MAF≥10% within the regions of interest based on Utah residents with Northern and Western European ancestry from the CEPH collection in the HapMap project.</p>3<p>Because no assays were available for the potentially functionally SNPs, the SNPs rs6475526, rs1874327 and rs2856968, respectively, were genotyped instead.</p><p>Polymorphisms evaluated in this study.</p

Kaplan-Meier analysis of survival according to genotypes of SNPs rs6475526, located 5′ to IFNA14, and capturing two IFN7 promoter SNPs and rs7047687 located in IFNA21 promoter.

<p>(A) Overall survival among all colorectal cancer patients (rs6475526, n = 465). (B) Event-free survival among patients without distant metastasis at diagnosis (rs6477526, n = 310). (C) Overall survival among all colorectal cancer patients (rs7047687, n = 464).</p