Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

1st Faculty of Medicine Institute of Hygiene and Epidemiology Charles University Prague Czech Republic

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

Brigham and Women's Hospital and VA Boston Boston MA USA

Brown University Providence RI USA

Cancer Epidemiology and Intelligence Division Cancer Council of Victoria 615 St Kilda Road Melbourne VIC 3004 Australia

Cancer Prevention Program Fred Hutchinson Cancer Research Center Seattle WA USA

Carol Davila University of Medicine and Pharmacy Th Burghele Hospital Bucharest Romania

Center 'Bioengineering' of the Russian Academy of Sciences Moscow Russian Federation

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Parkville Victoria 3010 Australia

Centre National de Recherche en Génomique Humaine Institut de biologie François Jacob CEA Evry France

CeRePP Paris France

CNRS UMR8200 Institute Gustave Roussy Villejuif France

College of Human Medicine Michigan State University Grand Rapids MI USA

Dana Farber Cancer Institute Bostan MA USA

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

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

Department of Epidemiology and Biostatistics School of Public Health Indiana University Bloomington Bloomington IN USA

Department of Epidemiology Division of Cancer Prevention and Population Sciences The University of Texas MD Anderson Cancer Center Houston TX USA

Department of Epidemiology Nofer Institute of Occupational Medicine Lodz Poland

Department of Oncology University of Cambridge Cambridge UK

Department of Preventive Medicine Faculty of Medicine Palacky University Olomouc Czech Republic

Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Public Health Section for Epidemiology Aarhus University Aarhus C Denmark

Department of Surgical and Perioperative Sciences Urology and Andrology Umeå University Umeå Sweden

Department of Urology University Hospital Dr D Misovic Clinical Center Belgrade Serbia

Dipartimento di Medicina Clinica e Chirurgia Federico 2 University Naples Italy

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Department Health and Human Services Bethesda MD USA

Division of Urology Spectrum Health Grand Rapids MI USA

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Faculty of Medicine School of Public Health Imperial College London London UK

Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain Paris France

Fred Hutchinson Cancer Research Center Seattle WA USA

Harvard T H Chan School of Public Health Boston MA USA

Hellenic Health Foundation Alexandroupoleos 23 Athens 11527 Greece

Inserm U1018 Center for Research in Epidemiology and Population Health Facultés de Medicine Université Paris Saclay Université Paris Sud UVSQ Gustave Roussy 114 rue Edouard Vaillant 94805 Villejuif Cedex France

INSERM U946 Paris France

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Pathology Medical school of Belgrade Belgrade Serbia

International Agency for Research on Cancer Lyon France

International Hereditary Cancer Center Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Kurchatov Scientific Center Moscow Russian Federation

Leeds Institute of Cancer and Pathology University of Leeds Cancer Research Building St James's University Hospital Leeds UK

London School of Hygiene and Tropical Medicine University of London London UK

Max Planck Institute for Demographic Research Rostock Germany

McGill University and Genome Quebec Innovation Centre Montreal Quebec Canada

National Institute for Health and Welfare Helsinki Finland

National Institute of Public Health Bucharest Romania

National Public Health Institute Budapest Hungary

Regional Authority of Public Health in BanskaBystrica BanskaBystrica Slovakia

Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

Sorbonne Université GRC no 5 ONCOTYPE URO AP HP Tenon Hospital Paris France

The M Sklodowska Curie Cancer Center and Institute of Oncology Warsaw Poland

Van Andel Research Institute Center for Cancer Genomics and Quantitative Biology Grand Rapids MI USA

Vanderbilt Ingram Cancer Center Nasville TN USA

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Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma

Sexual dimorphism in cancer: insights from transcriptional signatures in kidney tissue and renal cell carcinoma