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.
European journal of human genetics : EJHG. 2019 Jun 23 [Epub ahead of print]
Ruhina S Laskar, David C Muller, Peng Li, Mitchell J Machiela, Yuanqing Ye, Valerie Gaborieau, Matthieu Foll, Jonathan N Hofmann, Leandro Colli, Joshua N Sampson, Zhaoming Wang, Delphine Bacq-Daian, Anne Boland, Behnoush Abedi-Ardekani, Geoffroy Durand, Florence Le Calvez-Kelm, Nivonirina Robinot, Helene Blanche, Egor Prokhortchouk, Konstantin G Skryabin, Laurie Burdett, Meredith Yeager, Sanja Radojevic-Skodric, Slavisa Savic, Lenka Foretova, Ivana Holcatova, Vladimir Janout, Dana Mates, Stefan Rascu, Anush Mukeria, David Zaridze, Vladimir Bencko, Cezary Cybulski, Eleonora Fabianova, Viorel Jinga, Jolanta Lissowska, Jan Lubinski, Marie Navratilova, Peter Rudnai, Beata Świątkowska, Simone Benhamou, Geraldine Cancel-Tassin, Olivier Cussenot, Antonia Trichopoulou, Elio Riboli, Kim Overvad, Salvatore Panico, Borje Ljungberg, Raviprakash T Sitaram, Graham G Giles, Roger L Milne, Gianluca Severi, Fiona Bruinsma, Tony Fletcher, Kvetoslava Koppova, Susanna C Larsson, Alicja Wolk, Rosamonde E Banks, Peter J Selby, Douglas F Easton, Paul Pharoah, Gabriella Andreotti, Laura E Beane Freeman, Stella Koutros, Demetrius Albanes, Satu Männistö, Stephanie Weinstein, Peter E Clark, Todd L Edwards, Loren Lipworth, Hallie Carol, Matthew L Freedman, Mark M Pomerantz, Eunyoung Cho, Peter Kraft, Mark A Preston, Kathryn M Wilson, J Michael Gaziano, Howard D Sesso, Amanda Black, Neal D Freedman, Wen-Yi Huang, John G Anema, Richard J Kahnoski, Brian R Lane, Sabrina L Noyes, David Petillo, Bin Tean Teh, Ulrike Peters, Emily White, Garnet L Anderson, Lisa Johnson, Juhua Luo, Wong-Ho Chow, Lee E Moore, Toni K Choueiri, Christopher Wood, Mattias Johansson, James D McKay, Kevin M Brown, Nathaniel Rothman, Mark G Lathrop, Jean-Francois Deleuze, Xifeng Wu, Paul Brennan, Stephen J Chanock, Mark P Purdue, Ghislaine Scelo
International Agency for Research on Cancer (IARC), Lyon, France., Faculty of Medicine, School of Public Health, Imperial College London, London, UK., Max Planck Institute for Demographic Research, Rostock, Germany., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MD, USA., Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Centre National de Recherche en Génomique Humaine, , Institut de biologie François Jacob, CEA, Evry, France., Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France., Center 'Bioengineering' of the Russian Academy of Sciences, Moscow, Russian Federation., Institute of Pathology, Medical school of Belgrade, Belgrade, Serbia., Department of Urology, University Hospital "Dr D. Misovic" Clinical Center, Belgrade, Serbia., Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic., 2nd Faculty of Medicine, Institute of Public Health and Preventive Medicine, Charles University, Prague, Czech Republic., Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic., National Institute of Public Health, Bucharest, Romania., Carol Davila University of Medicine and Pharmacy, Th. Burghele Hospital, Bucharest, Romania., Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation., First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University, Prague, Czech Republic., International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland., Regional Authority of Public Health in BanskaBystrica, BanskaBystrica, Slovakia., The M Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland., National Public Health Institute, Budapest, Hungary., Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland., INSERM U946, Paris, France., Sorbonne Université, GRC no. 5, ONCOTYPE-URO, AP-HP, Tenon Hospital, Paris, France., Hellenic Health Foundation, Alexandroupoleos 23, Athens, 11527, Greece., Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus C, Denmark., Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy., Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden., Cancer Epidemiology & Intelligence Division, Cancer Council of Victoria, 615 St Kilda Road, Melbourne, VIC, 3004, Australia., London School of Hygiene and Tropical Medicine, University of London, London, UK., Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden., Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds, UK., Department of Oncology, University of Cambridge, Cambridge, UK., National Institute for Health and Welfare, Helsinki, Finland., Vanderbilt-Ingram Cancer Center, Nasville, TN, USA., Dana-Farber Cancer Institute, Bostan, MA, USA., Brown University, Providence, RI, USA., Harvard T.H. Chan School of Public Health, Boston, MA, USA., Brigham and Women's Hospital and VA Boston, Boston, MA, USA., Division of Urology, Spectrum Health, Grand Rapids, MI, USA., Van Andel Research Institute, Center for Cancer Genomics and Quantitative Biology, Grand Rapids, MI, USA., Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Epidemiology and Biostatistics, School of Public Health Indiana University Bloomington, Bloomington, IN, USA., McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada., International Agency for Research on Cancer (IARC), Lyon, France. .