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Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer.

ABSTRACT: 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.

SUBMITTER: Reid-Lombardo KM

PROVIDER: S-EPMC3677709 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer.

Reid-Lombardo Kaye M KM Fridley Brooke L BL Bamlet William R WR Cunningham Julie M JM Sarr Michael G MG Petersen Gloria M GM

Annals of surgery 20130601 6

<h4>Objective</h4>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.<h4>Summary background data</h4>Inflammation has been linked to PC. Reports have cited an increased expression of proinflammatory mediators, such as NF-κB and COX, in PC but not in normal adjacent tissue, suggesting a possible role in carcinogenesis. We sought to further u ...[more]

PMID: 23360921

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Project description:BackgroundKRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection.MethodsEligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed.ResultsTargeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P = .043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P = .012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P = .020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P = .035).ConclusionsIn patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.

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Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer.

Publications

Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer.

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