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


BACKGROUND
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.
Division of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, MN 55905, USA. reidlombardo.kaye@mayo.edu
Kaye M
KM
Reid-Lombardo
Brooke L
BL
Fridley
William R
WR
Bamlet
Julie M
JM
Cunningham
Michael G
MG
Sarr
Gloria M
GM
Petersen
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D017526:Receptor, IGF Type 1 / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D015996:Survival Rate
D048868:Adaptor Proteins, Signal Transducing; C490666:MAPK8IP1 protein, human; D016328:NF-kappa B; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D017526:Receptor, IGF Type 1