The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10-5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk.

1st Faculty of Medicine Institute of Biology and Medical Genetics Charles University Prague Czech Republic

ARC NET Centre for Applied Research on Cancer University and Hospital Trust of Verona Verona Italy

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Florence Italy

Cancer Center Amsterdam Imaging and Biomarkers Amsterdam The Netherlands

Center for Translational Medicine Semmelweis University Budapest Hungary

Centre for Translational Medicine Department of Medicine University of Szeged Szeged Hungary

Centre for Translational Medicine Semmelweis University Budapest Hungary

Department DIMED Laboratory Medicine University of Padova Padua Italy

Department DISCOG University of Padova Padua Italy

Department of Biology University of Pisa 56126 Pisa Italy

Department of Biomedical Sciences Humanitas University Milan Italy

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

Department of General Surgery University of Heidelberg Heidelberg Germany

Department of General Visceral and Thoracic Surgery University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Medical Oncology Amsterdam UMC Location University of Amsterdam Meibergdreef 9 Amsterdam The Netherlands

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Oncology Faculty of Medicine and Dentistry Palacký University Olomouc Czech Republic

Department of Surgery Erasmus MC University Medical Center Rotterdam The Netherlands

Digestive and Liver Disease Unit Sant'Andrea Hospital Rome Italy

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Gastroenterology and Research Laboratory Fondazione IRCCS Casa Sollievo Della Sofferenza Hospital San Giovanni Rotondo Italy

Division of General and Transplant Surgery Pisa University Hospital Pisa Italy

Division of Pancreatic Diseases Heart and Vascular Center Semmelweis University Budapest Hungary

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Gastroenterology and Gastrointestinal Endoscopy Unit Vita Salute San Raffaele University IRCCS San Raffaele Scientific Institute Milan Italy

Gastroenterology Department and Institute for Digestive Research Lithuanian University of Health Sciences Kaunas Lithuania

General Surgery Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa Pisa Italy

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

German Cancer Consortium Heidelberg Germany

Institute for Translational Medicine Medical School University of Pécs Pécs Hungary

János Szentágothai Research Center University of Pécs Pécs Hungary

Laboratory for Applied Science and Technology in Health Carlos Chagas Institute Oswaldo Cruz Foundation Curitiba Brazil

Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece

Medical Faculty Heidelberg Heidelberg University Heidelberg Germany

Network Aging Research Heidelberg University Heidelberg Germany

Oncology of Massa Carrara Oncological Department Azienda USL Toscana Nord Ovest Carrara Italy

Pancreatic Surgery Unit IRCCS Humanitas Research Hospital Milan Italy

Pancreato Biliary Endoscopy and Endoscopic Ultrasound Pancreas Translational and Clinical Research Center San Raffaele Scientific Institute IRCCS Milan Italy

Potenza Medical County Association Potenza Italy

Surgery Clinic 3rd Faculty of Medicine Charles University Prague Czech Republic

University of Utrecht Utrecht The Netherlands

See more in PubMed

Rahib L, et al. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the united states. Cancer Res. 2014;74:2913–2921. PubMed

Ferlay J, et al. Cancer statistics for the year 2020: An overview. Int. J. Cancer. 2021;149:778–789. PubMed

Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J. Clin. 2021;71:209–249. PubMed

Pourshams A, et al. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. Gastroenterol. Hepatol. 2019;4:934–947. PubMed PMC

Sumi C, Brinck-Johnsen T, Longnecker DS. Inhibition of a transplantable pancreatic carcinoma by castration and estradiol administration in rats. Cancer Res. 1989;49:6687–6692. PubMed

Santen RJ, et al. Postmenopausal hormone therapy: An endocrine society scientific statement. J. Clin. Endocrinol. Metab. 2010;95:s1–s66. PubMed PMC

Wahi MM, Shah N, Schrock CE, Rosemurgy AS, Goldin SB. Reproductive factors and risk of pancreatic cancer in women: A review of the literature. Ann. Epidemiol. 2009;19:103–111. PubMed

Michels KA, Brinton LA, Pfeiffer RM, Trabert B. Oral contraceptive use and risks of cancer in the NIH-AARP diet and health study. Am. J. Epidemiol. 2018;187:1630. PubMed PMC

Teng Y, et al. Female reproductive factors, exogenous hormone use, and pancreatic cancer risk: The Japan Public Health Center-based prospective study. Eur. J. Cancer Prev. 2017;26:378–384. PubMed

Andersson G, Borgquist S, Jirström K. Hormonal factors and pancreatic cancer risk in women: The Malmö Diet and Cancer Study. Int. J. Cancer. 2018;143:52–62. PubMed PMC

Sadr-Azodi O, Konings P, Brusselaers N. Menopausal hormone therapy and pancreatic cancer risk in women: A population-based matched cohort study. United Eur. Gastroenterol. J. 2017;5:1123–1128. PubMed PMC

Butt SA, et al. Hormonal contraceptive use and risk of pancreatic cancer—A cohort study among premenopausal women. PLoS ONE. 2018;13:e0206358. PubMed PMC

Kabat GC, Kamensky V, Rohan TE. Reproductive factors, exogenous hormone use, and risk of pancreatic cancer in postmenopausal women. Cancer Epidemiol. 2017;49:1–7. PubMed

Tang B, et al. Relationship between female hormonal and menstrual factors and pancreatic cancer: A meta-analysis of observational studies. Medicine Baltimore. 2015;94:e177. PubMed PMC

Amundadottir L, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat. Genet. 2009;41:986–990. PubMed PMC

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

Yang W, et al. Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk. Cancer Sci. 2019;20:32. doi: 10.1111/cas.14017. PubMed DOI PMC

Gentiluomo M, Peduzzi G, Lu Y, Campa D, Canzian F. Genetic polymorphisms in inflammatory genes and pancreatic cancer risk: A two-phase study on more than 14 000 individuals. Mutagenesis. 2019;34:395–401. PubMed

Campa D, et al. Genome-wide association study identifies an early onset pancreatic cancer risk locus. Int. J. Cancer. 2020;147:2065–2074. PubMed

Gentiluomo M, et al. Germline genetic variability in pancreatic cancer risk and prognosis. Semin. Cancer Biol. 2020 doi: 10.1016/j.semcancer.2020.08.003. PubMed DOI

Corradi C, et al. Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility. Int. J. Cancer. 2021;148:2779–2788. PubMed

Rizzato C, et al. ABO blood groups and pancreatic cancer risk and survival: Results from the PANcreatic Disease ReseArch (PANDoRA) consortium. Oncol. Rep. 2013;29:1637–1644. PubMed

Wolpin BM, et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat. Genet. 2014;46:994–1000. PubMed PMC

Childs EJ, et al. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. Nat. Genet. 2015;47:911–916. PubMed PMC

Campa D, et al. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. Int. J. Cancer. 2015;137:2175–2183. PubMed PMC

Campa D, et al. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk. Oncotarget. 2016;7:57011–57020. PubMed PMC

Zhang M, et al. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. Oncotarget. 2016;7:35. PubMed PMC

Klein, A. P. et al. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat. Commun.9, (2018). PubMed PMC

Xu X, et al. Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk. Mol. Carcinog. 2019;58:1338–1348. PubMed PMC

Larsson SC, et al. Serum estradiol and 20 Site-specific cancers in women: Mendelian randomization study. J. Clin. Endocrinol. Metab. 2022;107:e467. PubMed PMC

Johnson N, et al. CYP3A7*1C allele: Linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers. Br. J. Cancer. 2021;124:842. PubMed PMC

Cote ML, et al. Tobacco and estrogen metabolic polymorphisms and risk of non-small cell lung cancer in women. Carcinogenesis. 2009;30:626. PubMed PMC

Tang L, et al. Associations between polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: Results from the Prostate Cancer Prevention Trial. Carcinogenesis. 2018;39:125. PubMed PMC

Quan L, et al. Variants in estrogen-related genes and breast cancer risk in European and African American women. Endocr. Relat. Cancer. 2014;21:853. PubMed PMC

Freedman ND, et al. Polymorphisms in estrogen- and androgen-metabolizing genes and the risk of gastric cancer. Carcinogenesis. 2009;30:71. PubMed PMC

Galeotti AA, et al. Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction. J. Med. Genet. 2021;58:369–377. PubMed

Zhang Y, Coogan PF, Palmer JR, Strom BL, Rosenberg L. A case–control study of reproductive factors, female hormone use, and risk of pancreatic cancer. Cancer Causes Control. 2010;21:473. PubMed PMC

Lee E, et al. Reproductive factors, exogenous hormones, and pancreatic cancer risk in the CTS. Am. J. Epidemiol. 2013;178:1403–1413. PubMed PMC

Chen KY, et al. Estrogen receptor gene polymorphisms and lung adenocarcinoma risk in never-smoking women. J. Thorac. Oncol. 2015;10:1413–1420. PubMed

Lee, Y. Liver receptor homolog-1, an emerging metabolic modulator. Front. Biosci. 5950 (2008). PubMed

Chen Q, et al. Association between NR5A2 and the risk of pancreatic cancer, especially among Caucasians: A meta-analysis of case–control studies. Onco. Targets. Ther. 2018;11:2709–2723. PubMed PMC

von Figura G, Morris JP, Wright CVE, Hebrok M. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut. 2014;63:656–664. PubMed PMC

Campa D, et al. Genetic variability of the forkhead box O3 and prostate cancer risk in the European Prospective Investigation on Cancer. Oncol. Rep. 2011;26:979–986. PubMed

Noordam, R. et al. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. Nat. Commun.10, (2019). PubMed PMC

Liu S, et al. Integration of transcriptome and cistrome analysis identifies RUNX1-target genes involved in pancreatic cancer proliferation. Genomics. 2020;112:5343–5355. PubMed

Rohira AD, Lonard DM. Steroid receptor coactivators present a unique opportunity for drug development in hormone-dependent cancers. Biochem. Pharmacol. 2017;140:1–7. PubMed

Park SK, et al. Polymorphisms of estrogen receptors and risk of biliary tract cancers and gallstones: A population-based study in Shanghai, China. Carcinogenesis. 2010;31:842–846. PubMed PMC

Lin J, et al. Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women. Cancer Causes Control. 2010;21:897–908. PubMed PMC

Gillespie M, et al. The reactome pathway knowledgebase 2022. Nucleic Acids Res. 2022;50:D687–D692. PubMed PMC

Petersen GM, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat. Genet. 2010;42:224–228. PubMed PMC

Chang CC, et al. Second-generation PLINK: Rising to the challenge of larger and richer datasets. Gigascience. 2015;4:1–16. PubMed PMC

Campa D, et al. Genetic susceptibility to pancreatic cancer and its functional characterisation: The PANcreatic Disease ReseArch (PANDoRA) consortium. Dig. Liver Dis. 2013;45:95–99. PubMed

Riboli E, et al. European Prospective Investigation into Cancer and Nutrition (EPIC): Study populations and data collection. Public Health Nutr. 2002;5:1113–1124. PubMed

Löw M, Stegmaier C, Ziegler H, Rothenbacher D, Brenner H. Epidemiologische studie zu chancen der verhütung, früherkennung und optimierten therapie chronischer erkrankungen in der älteren bevölkerung (ESTHER-studie) Dtsch. Medizinische Wochenschrift. 2004;129:2643–2647. PubMed

de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: Generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 2015;11:e1004219. PubMed PMC