Geographic variation of mutagenic exposures in kidney cancer genomes

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures which make a substantial contribution to cancer burden, vary geographically, and have underlying agents thus far unidentified by conventional epidemiology[1][1]. This pertains to clear cell renal cell carcinomas (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence[2][2]. Some carcinogens generate somatic mutations and past exposures can be inferred from the patterns of mutations found in cancer genomes. Therefore, we sequenced the whole genomes of 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in >70% cases and <2% elsewhere. Another mutational signature of unknown cause was ubiquitous and associated with kidney cancer incidence rates (p-value<6 × 10−18), with higher numbers of mutations in countries with higher risk. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, widespread, geographically variable mutagenic exposures to known and unknown agents, which may contribute to the incidence of kidney cancer. ### Competing Interest Statement LBA is a compensated consultant and has equity interest in io9, LLC and Genome Insight. His spouse is an employee of Biotheranostics, Inc. LBA is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. ENB and LBA declare U.S. provisional applications with serial numbers: 63/289,601; 63/269,033; and 63/483,237. LBA also declares U.S. provisional applications with serial numbers: 63/366,392; 63/367,846; 63/412,835; and 63/492,348. VM received honoraria from Ipsen, Bayer, AstraZeneca, Janssen, Astellas Pharm and MSD, and provided expert testimony to BMS, Bayer, MSD and Janssen. No other authors declare any competing interests. ### Funding Statement This work was delivered as part of the Mutographs team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (C98/A24032). This work was supported by the Wellcome Trust grants 206194 and 220540/Z/20/A. The work was also partly funded by Barretos Cancer Hospital, the Public Ministry of Labor of Campinas (Research, Prevention, and Education of Occupational Cancer, 2015 to R.M.R.), and by Hospital de Clinicas de Porto Alegre (180330 to P.A.-P., M.B., B.S.N.). The work was also partly supported by the Practical Research Project for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) (JP20ck0106547h0001 to T.S.), and by the National Cancer Center Japan Research and Development Fund (2020-A-7 to A.F.). The work was also partly funded by the 1st and 2nd Faculties of Medicine, Charles University, Prague (CAGEKID to I.H.; Occupation, Environment and Kidney Cancer in Central and Eastern Europe to A.H.). The work was also partly supported by the Ministry of Health of the Czech Republic (MH CZ - DRO (MMCI, 00209805) to L.F. and M.N.). Measurement of PFAS compounds was funded by Division of Cancer Epidemiology and Genetics of the National Cancer Institute (USA). Measurement of cystatin C was funded by Cancer Research UK (C18281/A29019). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approvals were first obtained from each Local Research Ethics Committee and Federal Ethics Committee when applicable, as well as from the IARC Ethics Committee (IRB number: IEC Project 17-10) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Whole genome sequencing data and patient metadata are deposited in the European Genome-phenome Archive (EGA) associated with study EGAS00001003542. All other data are provided in the accompanying Supplementary Tables. [1]: #ref-1 [2]: #ref-2