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Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer.

  • Author(s): Li, Donghui;
  • Duell, Eric J;
  • Yu, Kai;
  • Risch, Harvey A;
  • Olson, Sara H;
  • Kooperberg, Charles;
  • Wolpin, Brian M;
  • Jiao, Li;
  • Dong, Xiaoqun;
  • Wheeler, Bill;
  • Arslan, Alan A;
  • Bueno-de-Mesquita, H Bas;
  • Fuchs, Charles S;
  • Gallinger, Steven;
  • Gross, Myron;
  • Hartge, Patricia;
  • Hoover, Robert N;
  • Holly, Elizabeth A;
  • Jacobs, Eric J;
  • Klein, Alison P;
  • LaCroix, Andrea;
  • Mandelson, Margaret T;
  • Petersen, Gloria;
  • Zheng, Wei;
  • Agalliu, Ilir;
  • Albanes, Demetrius;
  • Boutron-Ruault, Marie-Christine;
  • Bracci, Paige M;
  • Buring, Julie E;
  • Canzian, Federico;
  • Chang, Kenneth;
  • Chanock, Stephen J;
  • Cotterchio, Michelle;
  • Gaziano, J Michael;
  • Giovannucci, Edward L;
  • Goggins, Michael;
  • Hallmans, Göran;
  • Hankinson, Susan E;
  • Hoffman Bolton, Judith A;
  • Hunter, David J;
  • Hutchinson, Amy;
  • Jacobs, Kevin B;
  • Jenab, Mazda;
  • Khaw, Kay-Tee;
  • Kraft, Peter;
  • Krogh, Vittorio;
  • Kurtz, Robert C;
  • McWilliams, Robert R;
  • Mendelsohn, Julie B;
  • Patel, Alpa V;
  • Rabe, Kari G;
  • Riboli, Elio;
  • Shu, Xiao-Ou;
  • Tjønneland, Anne;
  • Tobias, Geoffrey S;
  • Trichopoulos, Dimitrios;
  • Virtamo, Jarmo;
  • Visvanathan, Kala;
  • Watters, Joanne;
  • Yu, Herbert;
  • Zeleniuch-Jacquotte, Anne;
  • Amundadottir, Laufey;
  • Stolzenberg-Solomon, Rachael Z
  • et al.

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Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

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