Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.
Nature genetics. 2024 Apr 26 [Epub ahead of print]
Mark P Purdue, Diptavo Dutta, Mitchell J Machiela, Bryan R Gorman, Timothy Winter, Dayne Okuhara, Sara Cleland, Aida Ferreiro-Iglesias, Paul Scheet, Aoxing Liu, Chao Wu, Samuel O Antwi, James Larkin, Stênio C Zequi, Maxine Sun, Keiko Hikino, Ali Hajiran, Keith A Lawson, Flavio Cárcano, Odile Blanchet, Brian Shuch, Kenneth G Nepple, Gaëlle Margue, Debasish Sundi, W Ryan Diver, Maria A A K Folgueira, Adrie van Bokhoven, Florencia Neffa, Kevin M Brown, Jonathan N Hofmann, Jongeun Rhee, Meredith Yeager, Nathan R Cole, Belynda D Hicks, Michelle R Manning, Amy A Hutchinson, Nathaniel Rothman, Wen-Yi Huang, W Marston Linehan, Adriana Lori, Matthieu Ferragu, Merzouka Zidane-Marinnes, Sérgio V Serrano, Wesley J Magnabosco, BioBank Japan Project , Ana Vilas, Ricardo Decia, Florencia Carusso, Laura S Graham, Kyra Anderson, Mehmet A Bilen, Cletus Arciero, Isabelle Pellegrin, Solène Ricard, FinnGen , Ghislaine Scelo, Rosamonde E Banks, Naveen S Vasudev, Naeem Soomro, Grant D Stewart, Adebanji Adeyoju, Stephen Bromage, David Hrouda, Norma Gibbons, Poulam Patel, Mark Sullivan, Andrew Protheroe, Francesca I Nugent, Michelle J Fournier, Xiaoyu Zhang, Lisa J Martin, Maria Komisarenko, Timothy Eisen, Sonia A Cunningham, Denise C Connolly, Robert G Uzzo, David Zaridze, Anush Mukeria, Ivana Holcatova, Anna Hornakova, Lenka Foretova, Vladimir Janout, Dana Mates, Viorel Jinga, Stefan Rascu, Mirjana Mijuskovic, Slavisa Savic, Sasa Milosavljevic, Valérie Gaborieau, Behnoush Abedi-Ardekani, James McKay, Mattias Johansson, Larry Phouthavongsy, Lindsay Hayman, Jason Li, Ilinca Lungu, Stephania M Bezerra, Aline G Souza, Claudia T G Sares, Rodolfo B Reis, Fabio P Gallucci, Mauricio D Cordeiro, Mark Pomerantz, Gwo-Shu M Lee, Matthew L Freedman, Anhyo Jeong, Samantha E Greenberg, Alejandro Sanchez, R Houston Thompson, Vidit Sharma, David D Thiel, Colleen T Ball, Diego Abreu, Elaine T Lam, William C Nahas, Viraj A Master, Alpa V Patel, Jean-Christophe Bernhard, Neal D Freedman, Pierre Bigot, Rui M Reis, Leandro M Colli, Antonio Finelli, Brandon J Manley, Chikashi Terao, Toni K Choueiri, Dirce M Carraro, Richard Houlston, Jeanette E Eckel-Passow, Philip H Abbosh, Andrea Ganna, Paul Brennan, Jian Gu, Stephen J Chanock
Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. ., Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Booz Allen Hamilton Inc, McLean, VA, USA., Laboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France., Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland., Biosample Repository, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA., Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, UK., Department of Urology, A.C. Camargo Cancer Center, São Paulo, Brazil., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Department of Urology, Division of Urologic Oncology, West Virginia University Cancer Institute, Morgantown, WV, USA., Department of Surgical Oncology, Division of Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Department of Medical Oncology, Barretos Cancer Hospital, Barretos, Brazil., Biobank Resource Centre, CHU Angers, Angers, France., Department of Urology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA., Department of Urology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA., Department of Urology, CHU Bordeaux, Bordeaux, France., Department of Urology, The Ohio State University Wexner Medical Center, Columbus, OH, USA., Department of Population Science, American Cancer Society, Atlanta, GA, USA., Departments of Radiology and Oncology, Comprehensive Center for Precision Oncology-C2PO, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas, Faculdade de Medicina Universidade de São Paulo, São Paulo, Brazil., Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Tumor Bank, Hospital Militar, Montevideo, Uruguay., Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Cancer Genomics Research Laboratory, Frederick National Laboratory, Rockville, MD, USA., Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Department of Urology, CHU Angers, Angers, France., Department of Pathology, CHU Angers, Angers, France., Department of Urology, Barretos Cancer Hospital, Barretos, Brazil., Department of Pathology, Hospital Pasteur, Montevideo, Uruguay., Department of Urology, Hospital Pasteur, Montevideo, Uruguay., Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Oncology Clinical Research Support Team, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA., Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA., Biobank, Bordeaux Biothèque Santé, CHU Bordeaux, Bordeaux, France., Observational and Pragmatic Research Institute Pte Ltd, Singapore, Singapore., Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK., Department of Oncology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK., Department of Urology, Newcastle Hospitals NHS Foundation Trust, Newcastle, UK., Department of Urology, Western General Hospital, NHS Lothian, Edinburgh, UK., Department of Urology, Stockport NHS Foundation Trust, Stockport, UK., Department of Urology, Imperial College Healthcare NHS Trust, London, UK., Division of Oncology, University of Nottingham, Nottingham, UK., Department of Urology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Tissue Core, Moffitt Cancer Center, Tampa, FL, USA., Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Cancer Signaling and Microenvironment, Biosample Repository Facility, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA., Department of Urology, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA., Department of Clinical Epidemiology, N.N. Blokhin National Medical Research Centre of Oncology, Moscow, Russia., Institute of Public Health and Preventive Medicine, Second Faculty of Medicine, Charles University, Prague, Czech Republic., Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University, Prague, Czech Republic., Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic., Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic., Department of Occupational Health and Toxicology, National Center for Environmental Risk Monitoring, National Institute of Public Health, Bucharest, Romania., Urology Department, Academy of Romanian Scientists, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania., Urology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania., Clinic of Nephrology, Faculty of Medicine, Military Medical Academy, Belgrade, Serbia., Department of Urology, Clinical Hospital Center Dr Dragisa Misovic Dedinje, Belgrade, Serbia., International Organisation for Cancer Prevention and Research, Belgrade, Serbia., Ontario Tumour Bank, Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Diagnostic Development Program, Tissue Portal, Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil., Departments of Medical Imaging, Hematology and Oncology, Division of Medical Oncology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil., Departments of Surgery and Anatomy, Division of Urology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil., Surgery Department, Urology Division, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Dana-Farber Cancer Institute, Boston, MA, USA., Department of Population Sciences, Genetic Counseling Shared Resource, Huntsman Cancer Institute, Salt Lake City, UT, USA., Department of Surgery, Division of Urology, Huntsman Cancer Institute and University of Utah, Salt Lake City, UT, USA., Department of Urology, Mayo Clinic, Rochester, MN, USA., Department of Urology, Mayo Clinic, Jacksonville, FL, USA., Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA., Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil., Departament of Medical Image, Hematology and Oncology, Division of Medical Oncology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil., Genitourinary Oncology Program, Moffitt Cancer Center, Tampa, FL, USA., Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Clinical and Functional Genomics Group, CIPE (International Research Center), A.C. Camargo Cancer Center, São Paulo, Brazil., Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK., Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Department of Nuclear Dynamics and Cancer, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA., Laboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. .