Citations

Abstract Introduction Pancreatic cancer is a highly lethal malignancy due to late diagnosis and aggressiveness of the tumor. Characterization of high-risk populations for monitoring, intervention and early detection remains challenging. Obesity and diabetes are potentially modifiable contributors to pancreatic cancer. Genetic factors modifying the risk of obesity- and diabetes-induced pancreatic cancer have previously not been fully investigated at the genome-wide level. Hypothesis There are potential genetic factors modifying the associations between obesity/diabetes and pancreatic cancer. Methods Integrating genotype with risk factor data from a GWAS for the Pancreatic Cancer Case Control Consortium, we performed a genome-wide gene-environment interaction (G x E) scan for 457,688 SNPs in a discovery study of 2,028 cases and 2,109 controls using state-of-the-art methods including case-only (CO), case-control (CC), Empirical Hierarchical Bayes (EHB), Empirical-Bayes test (EB) and three 2-step approaches (DG2, EG2, DGEG2). Results We detected a genome-wide significant (P < 1.09 x 10-7 ) interaction of diabetes with rs13061928 (in CNTN4) in CO (P = 8.8 x 10-8 ), which was independent of diabetes in control group (P = 0.08). The minor allele was in a synergism with diabetes on the cancer risk: diabetics carrying GA/AA genotype had a 3.39-fold (95% CI: 2.47-4.65) increased disease risk compared with non-diabetics carrying GG genotype. Consistently, the SNP-diabetes interaction had a high ranking statistic in EHB (No.1) and high p-value ranks for EG2 and DGEG2 methods (No.1, P= 5.44 x 10-5). Conclusions These observations, once validated/confirmed, may help define at-risk subpopulation and initiate targeted intervention and prevention of pancreatic cancer. Genome-wide G x E analysis requires larger sample size than genetic main effects scan; combining the CO method with alternative methods may be the optimal scheme for genome-wide G x E analysis. Citation Format: Hongwei Tang, Eric J. Duell, Harvey A. Risch Risch, Sara H. Olson, H. Bas Bueno-de-Mesquita, Steven Gallinger, Elizabeth A. Holly, Gloria M. Petersen, Paige M. Bracci, Robert R. McWilliams, Mazda Jenab, Elio Riboli, Anne Tjønneland, Marie Christine Boutron-Ruault, Rudolf Kaaks, Dimitrios Trichopoulos, Salvatore Panico, Malin Sund, Petra H. M Peeters, Kay-Tee Khaw, Christopher I Amos, Donghui Li, Peng Wei. Genome-wide gene-diabetes and gene-obesity interaction scan in the pancreatic cancer case control consortium. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2214. doi:10.1158/1538-7445.AM2014-2214

Background and objective Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. Methods We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10 −5 ) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). Results In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10 −7 ), rs981621 (p=1.65×10 −7 ) and rs16861827 (p=3.75×10 −7 ), respectively. 131 SNPs with p≤10 −5 were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10 −7 ) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. Conclusions Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.