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

Abstract

Objective: 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.

Summary background data: 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 understand the role that genetic variants in the NF-κB inflammatory pathway play in the development and progression of PC.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1

Kaplan Meier survival curve, Dominant Model: Gene: MAPK8IP1, SNP rs3824872, Group: Resected

Figure 2

Kaplan Meier survival curve, Dominant Model: Gene: SOCS3, SNP rs8064821, Group: Resected

Figure 3

Kaplan Meier survival curve, Dominant Model: Gene: PTGFRN, SNP rs6688746, Group: Resected

Figure 4

Kaplan Meier survival curve, Dominant Model: Gene: PTGFRN, SNP rs1153422, Group: Resected