BACKGROUND: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

Boston VA Healthcare System Boston MA

Cancer Care Ontario University of Toronto Toronto ON Canada

Cancer Epidemiology and Intelligence Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Epidemiology Program University of Hawaii Cancer Center Honolulu HI

Centre de Recherche en Épidémiologie et Santé des Populations Facultés de Medicine Université Paris Saclay UPS UVSQ Gustave Roussy Villejuif France

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Victoria Australia

CIBER Epidemiología y Salud Pública Barcelona Spain

CIBERONC Madrid Spain

Dalla Lana School of Public Health University of Toronto Toronto ON Canada

Departament de Ciències Experimentals i de la Salut Universitat Pompeu Fabra Barcelona Spain

Department for Determinants of Chronic Diseases Bilthoven the Netherlands

Department of Biostatistics Harvard School of Public Health Boston MA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Chronic Disease Epidemiology Yale School of Public Health New Haven CT

Department of Community Medicine Faculty of Health Sciences University of Tromsø The Arctic University of Norway Tromsø Norway

Department of Computational Biology St Jude Children's Research Hospital Memphis Tennessee

Department of Environmental Medicine New York University School of Medicine New York NY

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK

Department of Epidemiology and Biostatistics University of California San Francisco CA

Department of Epidemiology and Environmental Health University at Buffalo Buffalo NY

Department of Epidemiology and Preventive Medicine Monash University Melbourne Victoria Australia

Department of Epidemiology and Public Health Faculty of Medicine University of Ostrava Czech Republic

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD

Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX

Department of Epidemiology University of Washington Seattle WA

Department of Gastrointestinal Medical Oncology University of Texas MD Anderson Cancer Center Houston TX

Department of General Surgery University Hospital Heidelberg Heidelberg Germany

Department of Health Sciences Research Mayo Clinic College of Medicine Rochester MN

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Oncology Dana Farber Cancer Institute Boston MA

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Department of Obstetrics and Gynecology New York University School of Medicine New York NY

Department of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine Baltimore MD

Department of Pathology Sol Goldman Pancreatic Cancer Research Center Johns Hopkins School of Medicine Baltimore MD

Department of Population Health New York University School of Medicine New York NY

Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles CA

Department of Public Health Solutions National Institute for Health and Welfare Helsinki Finland

Department of Radiation Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine Baltimore MD

Department of Research Cancer Registry of Norway Institute of Population Based Cancer Research Oslo Norway

Department of Social and Preventive Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Department of Surgical and Perioperative Sciences Umeå University Umeå Sweden

Division of Aging Brigham and Women's Hospital Boston MA

Division of Applied Regulatory Science Office of Translational Science Center for Drug Evaluation and Research U S Food and Drug Administration Silver Spring MD

Division of Cancer Control and Population Sciences National Cancer Institute National Institutes of Health Bethesda MD

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD

Division of Epidemiology 2 Office of Surveillance and Epidemiology Center for Drug Evaluation and Research U S Food and Drug Administration Silver Spring MD

Division of Epidemiology Department of Medicine Vanderbilt Epidemiology Center Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville TN

Division of Hepatobiliary and Pancreas Surgery Mayo Clinic Rochester MN

Division of Preventive Medicine Brigham and Women's Hospital Boston MA

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA

Division of Research Kaiser Permanente Northern California Oakland CA

Epidemiology Research Program American Cancer Society Atlanta GA

Epithelial Carcinogenesis Group Spanish National Cancer Research Centre CNIO Madrid Spain

Faculty of Medicine University of Olomouc Olomouc Czech Republic

Genetic and Molecular Epidemiology Group Spanish National Cancer Research Center Madrid Spain

Genetic Epidemiology Group Folkhälsan Research Center and Faculty of Medicine University of Helsinki Helsinki Finland

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

Glickman Urological and Kidney Institute Cleveland Clinic Cleveland OH

Hospital del Mar Institute of Medical Research Universitat Autònoma de Barcelona Barcelona Spain

Information Management Systems Silver Spring MD

Institute of Public Health and Preventive Medicine Charles University 2nd Faculty of Medicine Prague Czech Republic

International Agency for Research on Cancer Lyon France

Laboratory of Translational Genomics Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD

MRC Epidemiology Unit University of Cambridge Cambridge UK

National Institute for Cellular Biotechnology Dublin City University Glasnevin Dublin Ireland

Perlmutter Cancer Center New York University School of Medicine New York NY

Population Health Department QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Prosserman Centre for Population Health Research Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto ON Canada

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle WA

Unit of Nutrition and Cancer Cancer Epidemiology Research Program Bellvitge Biomedical Research Institute Barcelona Spain

Yale Cancer Center New Haven CT

See more in PubMed

Jemal A, Ward EM, Johnson CJ, et al. Annual report to the nation on the status of cancer, 1975–2014, featuring survival. JNCI J Natl Cancer Inst. 2017;1099:1827–1839. PubMed PMC

Stolzenberg-Solomon RZ, Amundadottir LT.. Epidemiology and inherited predisposition for sporadic pancreatic adenocarcinoma. Hematol Oncol Clin North Am. 2015;294:619–640. PubMed PMC

Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;419:986–990. PubMed PMC

Petersen GM, Amundadottir L, Fuchs CS, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010;423:224–228. PubMed PMC

Wolpin BM, Rizzato C, Kraft P, et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet. 2014;469:994–1000. PubMed PMC

Childs EJ, Mocci E, Campa D, et al. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. Nat Genet. 2015;478:911–916. PubMed PMC

Zhang M, Wang Z, Obazee O, et al. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. Oncotarget. 2016;741:66328–66343. PubMed PMC

Klein AP, Wolpin BM, Risch HA, et al. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat Commun. 2018;91:556.. PubMed PMC

Wei P, Tang H, Li D.. Insights into pancreatic cancer etiology from pathway analysis of genome-wide association study data. PLoS One. 2012;710:e46887.. PubMed PMC

Li D, Duell EJ, Yu K, et al. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. Carcinogenesis. 2012;337:1384–1390. PubMed PMC

Zhang H, Wheeler W, Hyland PL, et al. A powerful procedure for pathway-based meta-analysis using summary statistics identifies 43 pathways associated with type II diabetes in European populations. PLoS Genet. 2016;126:e1006122. PubMed PMC

ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;4897414:57–74. PubMed PMC

Kundaje A, Meuleman W, Ernst J, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;5187539:317–330. PubMed PMC

Yates A, Akanni W, Amode MR, et al. Ensembl 2016. Nucleic Acids Res. 2016;44(D1):D710–D716. PubMed PMC

Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;229:1790–1797. PubMed PMC

Machiela MJ, Chanock SJ.. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;3121:3555–3557. PubMed PMC

Ward LD, Kellis M.. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016;44(D1):D877–D881. PubMed PMC

Ardlie KG, Deluca DS, Segre AV, et al. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;3486235:648–660. PubMed PMC

Zhang M, Lykke-Andersen S, Zhu B, et al. Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues. Gut. 2018;67(3):521–533. PubMed PMC

Pierce BL, Ahsan H.. Genome-wide “pleiotropy scan” identifies HNF1A region as a novel pancreatic cancer susceptibility locus. Cancer Res. 2011;7113:4352–4358. PubMed PMC

Luo Z, Li Y, Wang H, et al. Hepatocyte nuclear factor 1A (HNF1A) as a possible tumor suppressor in pancreatic cancer. PLoS One. 2015;103:e0121082.. PubMed PMC

Hoskins JW, Jia J, Flandez M, et al. Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. Carcinogenesis. 2014;3512:2670–2678. PubMed PMC

Maestro MA, Cardalda C, Boj SF, Luco RF, Servitja JM, Ferrer J, Distinct roles of HNF1β, HNF1α, and HNF4α in regulating pancreas development, β-cell function and growth In: Scharfmann R, Shield JPH, eds. Development of the Pancreas and Neonatal Diabetes. Vol 12 Basel: KARGER; 2007:33–45. PubMed

Zhang J, Qin X, Sun Q, et al. Transcriptional control of PAX4-regulated miR-144/451 modulates metastasis by suppressing ADAMs expression. Oncogene. 2015;3425:3283–3295. PubMed

Timsit J, Saint-Martin C, Dubois-Laforgue D, Bellanné-Chantelot C.. Searching for maturity-onset diabetes of the young (MODY): when and what for? Can J Diabetes. 2016;405:455–461. PubMed

Ullrich A, Prenzel N, Zwick E, et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 1999;4026764:884–888. PubMed

Fischer OM, Hart S, Gschwind A, Ullrich A.. EGFR signal transactivation in cancer cells. Biochem Soc Trans. 2003;31(pt 6):1203–1208. PubMed

Weil BR, Westby CM, Van Guilder GP, Greiner JJ, Stauffer BL, Desouza CA.. Enhanced endothelin-1 system activity with overweight and obesity. Am J Physiol Hear Circ Physiol. 2011;3013:H689–H695. PubMed PMC

Laurberg JR, Jensen JB, Schepeler T, Borre M, Ørntoft TF, Dyrskjøt L.. High expression of GEM and EDNRA is associated with metastasis and poor outcome in patients with advanced bladder cancer. BMC Cancer. 2014;14:638. PubMed PMC

Wülfing P, Götte M, Sonntag B, et al. Overexpression of endothelin-A-receptor in breast cancer: regulation by estradiol and cobalt-chloride induced hypoxia. Int J Oncol. 2005;264:951–960. PubMed

Nie S, Zhou J, Bai F, Jiang B, Chen J, Zhou J.. Role of endothelin A receptor in colon cancer metastasis: in vitro and in vivo evidence. Mol Carcinog. 2014;53(suppl 1):E85–E91. PubMed

Cook N, Brais R, Qian W, Chan Wah Hak C, Corrie PG.. Endothelin-1 and endothelin B receptor expression in pancreatic adenocarcinoma. J Clin Pathol. 2015;684:309–313. PubMed

Bhargava S, Stummeyer T, Hotz B, et al. Selective inhibition of endothelin receptor a as an anti-angiogenic and anti-proliferative strategy for human pancreatic cancer. J Gastrointest Surg. 2005;95:703–709. PubMed

Andreotti G, Boffetta P, Rosenberg PS, et al. Variants in blood pressure genes and the risk of renal cell carcinoma. Carcinogenesis. 2010;314:614–620. PubMed PMC

Wegman-Ostrosky T, Soto-Reyes E, Vidal-Millán S, Sánchez-Corona J.. The renin-angiotensin system meets the hallmarks of cancer. J Renin Angiotensin Aldosterone Syst. 2015;162:227–233. PubMed

Nikolsky Y, Sviridov E, Yao J, et al. Genome-wide functional synergy between amplified and mutated genes in human breast cancer. Cancer Res. 2008;6822:9532–9540. PubMed

Singh RR, Patel KP, Routbort MJ, et al. Clinical massively parallel next-generation sequencing analysis of 409 cancer-related genes for mutations and copy number variations in solid tumours. Br J Cancer. 2014;11110:2014–2023. PubMed PMC

Sahlberg KK, Hongisto V, Edgren H, et al. The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells. Mol Oncol. 2013;73:392–401. PubMed PMC

Pujana MA, Han J-DJ, Starita LM, et al. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet. 2007;3911:1338–1349. PubMed

Lavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008;910:759–769. PubMed

Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005;9711:813–822. PubMed

Marabelli M, Cheng S-C, Parmigiani G.. Penetrance of ATM gene mutations in breast cancer: a meta-analysis of different measures of risk. Genet Epidemiol. 2016;405:425–431. PubMed PMC

Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;21:41–46. PubMed PMC

Shindo K, Yu J, Suenaga M, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol. 2017;3530:3382–3390. PubMed PMC

Murakami-Tonami Y, Kishida S, Takeuchi I, et al. Inactivation of SMC2 shows a synergistic lethal response in MYCN -amplified neuroblastoma cells. Cell Cycle. 2014;137:1115–1131. PubMed PMC

Wang M-Y, Zhu M-L, He J, et al. Potentially functional polymorphisms in the CASP7 gene contribute to gastric adenocarcinoma susceptibility in an Eastern Chinese population. PLoS One. 2013;89:e74041.. PubMed PMC

Wang L, Jia P, Wolfinger RD, Chen X, Zhao Z.. Gene set analysis of genome-wide association studies: methodological issues and perspectives. Genomics. 2011;981:1–8. PubMed PMC

Fagny M, Paulson JN, Kuijjer ML, et al. Exploring regulation in tissues with eQTL networks. Proc Natl Acad Sci USA. 2017;11437:E7841–E7850. PubMed PMC

Veyrieras J-B, Kudaravalli S, Kim SY, et al. High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet. 2008;410:e1000214.. PubMed PMC

Freedman ML, Monteiro ANA, Gayther SA, et al. Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet. 2011;436:513–518. PubMed PMC

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B