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

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

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1384-1390
Number of pages7
JournalCarcinogenesis
Volume33
Issue number7
DOIs
StatePublished - Jul 2012

Bibliographical note

Funding Information:
The Yale University study was supported by grant number (5R01CA098870) from the NCI, NIH. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. This study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in this study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data.

Funding Information:
The PHS, NHS, HPFS and WHS at Harvard were supported by the NCI, NIH (grants no. P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, RO1 CA97193, RO1 CA34944, RO1 CA40360, RO1 HL26490, RO1 HL34595, RO1 CA047988, RO1 HL043851, RO1 HL080467).

Funding Information:
PLCO was supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), Pacific Health Research Institute (NO1-CN-25515), Henry Ford Health System (NO1-CN-25512), University of Minnesota (NO1-CN-25513), 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).

Funding Information:
This research was supported by the Intramural Research Program of the 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.

Funding Information:
This project has been funded in whole or in part with federal funds from the NCI, NIH, under Contract No. HHSN261200800001E.

Funding Information:
The Mayo Clinic Molecular Epidemiology of Pancreatic Cancer study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). The authors would like to acknowledge William Bamlet, Traci Hammer, Jodie Cogswell, Hugues Sicotte, Janet Olson, Martha Matsumoto, and Dennis Robinson.

Funding Information:
The Cancer Prevention Study II Nutrition Cohort is supported by the American Cancer Society. The authors thank all the men and women in the Cancer Prevention Study II Nutrition Cohort for their many years of dedicated participation in the study.

Funding Information:
CLUE II was supported by National Institute of Aging grant (5U01AG018033) and NCI grants (CA105069, CA73790). Cancer incidence data were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene, 201 W. Preston Street, Room 400, Baltimore, MD 21201, USA, www.fha.state.md.us/cancer/registry/, 410-767-4055. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data.

Funding Information:
The work at M. D. Anderson was supported by NIH grant (RO1 CA98380).

Funding Information:
The ATBC Study was supported by funding provided by the Intramural Research Program of the NCI, NIH and through US Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the NCI.

Funding Information:
The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32 and 44221.The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf.

Funding Information:
The NYU Women’s Health Study is supported by research grant (R01CA098661) and center grant (P30CA016087) from the NCI and the center grant (ES000260) from the National Institute of Environmental Health Sciences.

Funding Information:
The Shanghai Men’s Health Study was supported by the NCI extramural research grant (R01 CA82729). The Shanghai Women’s Health Study was supported by the NCI extramural research grant (R37 CA70867) and, partially for biological sample collection, by the Intramural Research Program of NCI (Division of Cancer Epidemiology and Genetics). We are in debt to the contributions of Drs Yu-Tang Gao and Yong-Bing Xiang in these two cohort studies. The studies would not be possible without the continuing support and devotion from the study participants and staff of the SMHS and SWHS.

Funding Information:
Pancreatic cancer research at Memorial Sloan-Kettering Cancer Center was supported by The Society of MSKCC and by the Geoffrey Beene Cancer Research Fund.

Funding Information:
The University of Toronto study was supported by grants from the NIH (R01 CA97075, as part of the PACGENE consortium), The Lustgarten Foundation for Pancreatic Cancer Research and the Ontario Cancer Research Network. We acknowledge the Pancreatic Cancer Canada Foundation (www.pancreaticcan-cercanada.ca) for their continued support of research into the early detection of pancreatic cancer and the Pancreas Cancer Screening Study at Mount Sinai Hospital and Princess Margaret Hospital. The authors acknowledge Ayelet Borgida and Heidi Rothenmund for their dedicated contributions toward data collection and study co-ordination.

Funding Information:
For the EPIC cohorts, all coauthors coordinated the initial recruitment and management of the studies. All authors contributed to the final paper. The authors thank all the participants who took part in this research and the funders and support and technical staff who made this study possible. The work described in this paper was carried out with the support of the European Commission: Public Health and Consumer Protection Directorate 1993–2004; Research Directorate-General 2005–2008.; Ligue contre le Cancer, Societé 3M, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center, Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); ISCIII RETIC (RD06/0020) of the Spanish Ministry of Health, The participating regional governments and institutions (Spain); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust (UK); Greek Ministry of Health and Social Solidarity, Hellenic Health Foundation and Stavros Niarchos Foundation (Greece); Italian Association for Research on Cancer (AIRC) (Italy); Dutch Ministry of Public Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands); Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane and Västerbotten (Sweden).

Funding Information:
The work at Johns Hopkins University was supported by the NCI (grants P50CA62924 and R01CA97075) and the Lustgarten Foundation for Pancreatic Cancer Research.

Funding Information:
The UCSF study was supported in part by NCI grants [CA59706, CA108370, CA109767, CA89726 (E.A.H., PI) and CA98889 (E.J.D., PI] and by the Rom-bauer Pancreatic Cancer Research Fund.

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