Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer.
Li, Donghui; Duell, Eric J. 1,+,++; Yu, Kai 2,+,++; Risch, Harvey A. 3,++; Olson, Sara H. 4,++; Kooperberg, Charles 5,++; Wolpin, Brian M. 6,7,++; Jiao, Li 8,++; Dong, Xiaoqun; Wheeler, Bill 9,++; Arslan, Alan A. 10,11,12; Bueno-de-Mesquita, H. Bas 13,14; Fuchs, Charles S. 6,7; Gallinger, Steven 15; Gross, Myron 16; Hartge, Patricia 2; Hoover, Robert N. 2; Holly, Elizabeth A. 17; Jacobs, Eric J. 18; Klein, Alison P. 19,20; LaCroix, Andrea 5; Mandelson, Margaret T. 5,21; Petersen, Gloria 22; Zheng, Wei 23; Agalliu, Ilir 24; Albanes, Demetrius 2; Boutron-Ruault, Marie-Christine 25; Bracci, Paige M. 17; Buring, Julie E. 26,27; Canzian, Federico 28; Chang, Kenneth 29; Chanock, Stephen J. 2,30,31; Cotterchio, Michelle 32,33; Gaziano, J.Michael 34; Giovannucci, Edward L. 7,35,36; Goggins, Michael 37; Hallmans, Goran 38; Hankinson, Susan E. 7,35; Hoffman Bolton, Judith A. 39; Hunter, David J. 7,35; Hutchinson, Amy 2,31; Jacobs, Kevin B. 2,31,40; Jenab, Mazda 41; Khaw, Kay-Tee 42; Kraft, Peter 35,43; Krogh, Vittorio 44; Kurtz, Robert C. 45; McWilliams, Robert R. 46; Mendelsohn, Julie B. 2; Patel, Alpa V. 18; Rabe, Kari G. 22; Riboli, Elio 47; Shu, Xiao-Ou 23; Tjonneland, Anne 48; Tobias, Geoffrey S. 2; Trichopoulos, Dimitrios 35,49; Virtamo, Jarmo 50; Visvanathan, Kala 37; Watters, Joanne 51; Yu, Herbert 3; Zeleniuch-Jacquotte, Anne 11,12; Amundadottir, Laufey 2,30,++,[S]; Stolzenberg-Solomon, Rachael Z. 2,++,[S],*
[Miscellaneous]
Carcinogenesis.
33(7):1384-1390, July 2012.
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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 x 10-6, 1.6 x 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 x 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.
(C) Copyright Oxford University Press 2012.
