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Genetic variation in inflammatory pathways is related to colorectal cancer survival.

ABSTRACT: Prognosis of patients with colorectal cancer (CRC) is associated with systemic inflammation, and anti-inflammatory drugs can reduce both CRC incidence and mortality. Genetic variation in proinflammatory pathways can affect an individual's CRC risk. However, few studies have investigated the prognostic importance of this genetic variation in CRC patients.We investigated the association between CRC survival and genetic variation in proinflammatory pathways among patients from the Puget Sound Surveillance Epidemiology and End Results registry. Single-nucleotide polymorphisms were genotyped in five genes (PTGS-1, PTGS-2, MRP4, NF?B, and I?BK?). Vital status was ascertained through linkage to the National Death Index. Cox proportional hazards regression was used to calculate HRs and 95% confidence intervals (CI). The false discovery rate method of Benjamini and Hochberg was applied to address multiple testing.Four PTGS-1 variants were associated with CRC survival. One, G>A intron 9 (rs1213266), was associated with approximately 50% lower CRC mortality (HR(AA/AG vs. GG) = 0.48; 95% CI, 0.25-0.93). Three variants, including L237M, resulted in significantly elevated CRC mortality risk, with HRs ranging from approximately 1.5 to 2.0. Two variants in I?BK?, including R526Q, were significantly associated with CRC survival. Correction for multiple testing indicated that variants in both PTGS-1 and I?BK? are reproducibly associated with CRC survival.Our findings suggest that genetic variation in proinflammatory pathways may be important for CRC prognosis. This investigation represents one of the first descriptions of the relationship between inherited polymorphisms and mortality in CRC patients and provides a starting point for further research.

SUBMITTER: Coghill AE

PROVIDER: S-EPMC3218294 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Genetic variation in inflammatory pathways is related to colorectal cancer survival.

Coghill Anna E AE Newcomb Polly A PA Poole Elizabeth M EM Hutter Carolyn M CM Makar Karen W KW Duggan Dave D Potter John D JD Ulrich Cornelia M CM

Clinical cancer research : an official journal of the American Association for Cancer Research 20111005 22

<h4>Purpose</h4>Prognosis of patients with colorectal cancer (CRC) is associated with systemic inflammation, and anti-inflammatory drugs can reduce both CRC incidence and mortality. Genetic variation in proinflammatory pathways can affect an individual's CRC risk. However, few studies have investigated the prognostic importance of this genetic variation in CRC patients.<h4>Experimental design</h4>We investigated the association between CRC survival and genetic variation in proinflammatory pathwa ...[more]

PMID: 21976545

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Project description:To test whether or not the association between inflammation and pancreatic ductal adenocarcinoma (PC) is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes.Inflammation has been linked to PC. Reports have cited an increased expression of proinflammatory mediators, such as NF-?B and COX, in PC but not in normal adjacent tissue, suggesting a possible role in carcinogenesis. We sought to further understand the role that genetic variants in the NF-?B inflammatory pathway play in the development and progression of PC.We genotyped 1536 tag single nucleotide polymorphisms (SNPs) in 102 candidate genes of multiple inflammatory pathways in 1308 white patients with PC who were divided into 3 groups on the basis of the extent of disease: resected for cure (n = 400), locally advanced/unresected (n = 443), and metastatic (n = 465). Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Statistical significance was set at less than 0.001 to control for multiple testing.Median age was 67 (28.0-91.0) years, and 57% were men. Median survival for each of the 3 groups (resected, locally advanced, and metastatic) was 23.7, 9.4, and 6.6 months, respectively (P < 0.0001). In the resected group, carriers of a minor allele for either rs3824872 (MAPK8IP1) or rs8064821 (SOCS3) were associated with a 10- and 6-month survival advantage compared with noncarriers in patients with resected disease, with an additional 2-year survival if both minor alleles were present. With locally advanced disease, SNP rs1124736 (IGF1R) was associated with improved survival if they had a copy of the G allele, hazard ratio of 0.57 (95% confidence interval: 0.42-0.77); P = 0.0002. In addition, 4 SNPs in patients with metastatic disease were found to be associated with worse survival and 2 associated with improved overall survival, but the differences in survival were deemed not clinically significant.SNPs in the inflammatory pathway genes MAPK8IP1 and SOCS3 were associated with increased overall survival in patients undergoing potentially curative resection and may be used in the future as markers to predict survival. Future research is needed to determine the functional relevance of these loci.

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Genetic variation in inflammatory pathways is related to colorectal cancer survival.

Publications

Genetic variation in inflammatory pathways is related to colorectal cancer survival.

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