Journal
CARCINOGENESIS
Volume 33, Issue 7, Pages 1384-1390Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgs151
Keywords
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Categories
Funding
- National Institutes of Health (NIH), Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services
- Insituto de Salud Carlos III (RETICC) [RD06/0020]
- NCI [R01CA098661, P30CA016087, P50CA62924, R01CA97075, R01 CA82729, R37 CA70867, CA59706, CA108370, CA109767, CA89726, CA98889, NO1-CN-25514, CA105069, CA73790]
- National Institute of Environmental Health Sciences [ES000260]
- National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]
- Mayo Clinic SPORE in Pancreatic Cancer [P50 CA102701]
- NCI, NIH [5R01CA098870, P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, RO1 CA97193, RO1 CA34944, RO1 CA40360, RO1 HL26490, RO1 HL34595, RO1 CA047988, RO1 HL043851, RO1 HL080467, HHSN261200800001E]
- Lustgarten Foundation for Pancreatic Cancer Research
- The Society of MSKCC
- Geoffrey Beene Cancer Research Fund
- NIH [RO1 CA98380]
- Rombauer Pancreatic Cancer Research Fund
- NIH (as part of the PACGENE consortium) [R01 CA97075]
- The Lustgarten Foundation for Pancreatic Cancer Research
- Ontario Cancer Research Network
- Georgetown University [NO1-CN25522]
- Pacific Health Research Institute [NO1-CN-25515]
- Henry Ford Health System [NO1-CN-25512]
- University of Minnesota [NO1-CN25513]
- Washington University [NO1-CN-25516]
- University of Pittsburgh [NO1-CN-25511]
- University of Utah [NO1-CN-25524]
- Marshfield Clinic Research Foundation [NO1-CN-25518]
- University of Alabama at Birmingham [NO1-CN-75022]
- Westat, Inc. [NO1-CN-25476]
- University of California, Los Angeles [NO1-CN-25404]
- NCI, NIH
- US Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004]
- European Commission: Public Health and Consumer Protection Directorate
- Ligue contre le Cancer
- Societe 3M
- Mutuelle Generale de l'Education Nationale
- Institut National de la Sante et de la Recherche Medicale (INSERM) (France)
- German Cancer Aid, German Cancer Research Center, Federal Ministry of Education and Research (Germany)
- Danish Cancer Society (Denmark)
- ISCIII RETIC of the Spanish Ministry of Health [RD06/0020]
- National Institute of Aging [5U01AG018033]
- State of Maryland
- Maryland Cigarette Restitution Fund
- National Program of Cancer Registries of the Centers for Disease Control and Prevention
- American Cancer Society
- Medical Research Council [G1000143, G0401527] Funding Source: researchfish
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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.
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