International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

Bevital AS Bergen Norway

Biomedical Sciences Graduate Program University of California San Diego La Jolla CA USA

Cancer Ageing and Somatic Mutation Wellcome Sanger Institute Cambridge UK

Cancer Epidemiology Unit The Nuffield Department of Population Health University of Oxford Oxford UK

Cancer Research UK Edinburgh Centre Institute of Genetics and Cancer University of Edinburgh Edinburgh UK

Centre for Biodiversity Genomics University of Guelph Guelph Ontario Canada

Clinic of Nephrology Faculty of Medicine Military Medical Academy Belgrade Serbia

Department of Anatomic Pathology A C Camargo Cancer Center São Paulo Brazil

Department of Bioengineering University of California San Diego La Jolla CA USA

Department of Botany and Genetics Institute of Biosciences Vilnius University Vilnius Lithuania

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

Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA

Department of Clinical Epidemiology N N Blokhin National Medical Research Centre of Oncology Moscow Russia

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Łódź Poland

Department of Epidemiology A C Camargo Cancer Center São Paulo Brazil

Department of Health Informatics Graduate School of Informatics Middle East Technical University Ankara Turkey

Department of Oncology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pathology Barretos Cancer Hospital Barretos Brazil

Department of Pathology Graduate School of Medicine The University of Tokyo Bunkyo ku Japan

Department of Pathology Radboud University Medical Centre Nijmegen Netherlands

Department of Surgery Division of Urology Sao Paulo Federal University São Paulo Brazil

Department of Urology A C Camargo Cancer Center São Paulo Brazil

Department of Urology Barretos Cancer Hospital Barretos Brazil

Department of Urology N N Blokhin National Medical Research Centre of Oncology Moscow Russia

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

Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD USA

Division of Cancer Genomics National Cancer Center Research Institute Chuo ku Japan

Division of Urology Department of Surgery Faculty of Medicine Prince of Songkla University Hat Yai Thailand

Evidence Synthesis and Classification Branch International Agency for Research on Cancer Lyon France

Experimental Research Center Genomic Medicine Laboratory Hospital de Clínicas de Porto Alegre Porto Alegre Brazil

Faculdade Ciências Médicas de Minas Gerais Belo Horizonte Brazil

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Genomic Epidemiology Branch International Agency for Research on Cancer Lyon France

Hasheminejad Kidney Center Iran University of Medical Sciences Tehran Iran

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

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

International Organization for Cancer Prevention and Research Belgrade Serbia

Laboratory of Genetic Diagnostic National Cancer Institute Vilnius Lithuania

Laboratory of Molecular Medicine The Institute of Medical Science The University of Tokyo Minato ku Japan

Latin American Renal Cancer Group São Paulo Brazil

Leeds Institute of Medical Research at St James's University of Leeds Leeds UK

Life and Health Sciences Research Institute School of Medicine Minho University Braga Portugal

Molecular Oncology Research Center Barretos Cancer Hospital Barretos Brazil

Moores Cancer Center University of California San Diego La Jolla CA USA

National Institute for Science and Technology in Oncogenomics and Therapeutic Innovation A C Camargo Cancer Center São Paulo Brazil

Nutrition and Metabolism Branch International Agency for Research on Cancer Lyon France

Observational and Pragmatic Research Institute Pte Ltd Singapore Singapore

Occupational Health and Toxicology Department National Center for Environmental Risk Monitoring National Institute of Public Health Bucharest Romania

Oncopathology Research Center Iran University of Medical Sciences Tehran Iran

Ontario Tumour Bank Ontario Institute for Cancer Research Toronto Ontario Canada

Post Graduate Program in Genetics and Molecular Biology Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Post Graduate Program in Medicine Surgical Sciences Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Service d'Anatomie Pathologique Assistance Publique Hôpitaux de Paris Univeristé Paris Saclay Le Kremlin Bicêtre France

Service of Urology Hospital de Clínicas de Porto Alegre Porto Alegre Brazil

Translational Medicine Research Center Faculty of Medicine Prince of Songkla University Hat Yai Thailand

Transplant Immunology and Personalized Medicine Unit Hospital de Clínicas de Porto Alegre Porto Alegre Brazil

Urology Department Carol Davila University of Medicine and Pharmacy Prof Dr Th Burghele Clinical Hospital Bucharest Romania

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The Mutographs biorepository: A unique genomic resource to study cancer around the world