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

ABSTRACT: 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.

SUBMITTER: Li D

PROVIDER: S-EPMC3405651 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Li Donghui D Duell Eric J EJ Yu Kai K Risch Harvey A HA Olson Sara H SH Kooperberg Charles C Wolpin Brian M BM Jiao Li L Dong Xiaoqun X Wheeler Bill B Arslan Alan A AA Bueno-de-Mesquita H Bas HB Fuchs Charles S CS Gallinger Steven S Gross Myron M Hartge Patricia P Hoover Robert N RN Holly Elizabeth A EA Jacobs Eric J EJ Klein Alison P AP LaCroix Andrea A Mandelson Margaret T MT Petersen Gloria G Zheng Wei W Agalliu Ilir I Albanes Demetrius D Boutron-Ruault Marie-Christine MC Bracci Paige M PM Buring Julie E JE Canzian Federico F Chang Kenneth K Chanock Stephen J SJ Cotterchio Michelle M Gaziano J Michael JM Giovannucci Edward L EL Goggins Michael M Hallmans Göran G Hankinson Susan E SE Hoffman Bolton Judith A JA Hunter David J DJ Hutchinson Amy A Jacobs Kevin B KB Jenab Mazda M Khaw Kay-Tee KT Kraft Peter P Krogh Vittorio V Kurtz Robert C RC McWilliams Robert R RR Mendelsohn Julie B JB Patel Alpa V AV Rabe Kari G KG Riboli Elio E Shu Xiao-Ou XO Tjønneland Anne A Tobias Geoffrey S GS Trichopoulos Dimitrios D Virtamo Jarmo J Visvanathan Kala K Watters Joanne J Yu Herbert H Zeleniuch-Jacquotte Anne A Amundadottir Laufey L Stolzenberg-Solomon Rachael Z RZ

Carcinogenesis 20120420 7

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 ca ...[more]

PMID: 22523087

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

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

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