Geographic variation of mutagenic exposures in kidney cancer genomes
Authors: Senkin Sergey , Moody Sarah , Díaz-Gay Marcos , Abedi-Ardekani Behnoush , Cattiaux Thomas , Ferreiro-Iglesias Aida , Wang Jingwei , Fitzgerald Stephen , Kazachkova Mariya , Vangara Raviteja , Le Anh Phuong , Bergstrom Erik N. , Khandekar Azhar , Otlu Burçak , Cheema Saamin , Latimer Calli , Thomas Emily , Atkins Joshua Ronald , Smith-Byrne Karl , Penha Ricardo Cortez Cardoso , Carreira Christine , Chopard Priscilia , Gaborieau Valérie , Keski-Rahkonen Pekka , Jones David , Teague Jon W. , Ferlicot Sophie , Asgari Mojgan , Sangkhathat Surasak , Attawettayanon Worapat , Świątkowska Beata , Jarmalaite Sonata , Sabaliauskaite Rasa , Shibata Tatsuhiro , Fukagawa Akihiko , Mates Dana , Jinga Viorel , Rascu Stefan , Mijuskovic Mirjana , Savic Slavisa , Milosavljevic Sasa , Bartlett John M.S. , Albert Monique , Phouthavongsy Larry , Ashton-Prolla Patricia , Botton Mariana R. , Neto Brasil Silva , Bezerra Stephania Martins , Curado Maria Paula , de Cássio Zequi Stênio , Reis Rui Manuel , Faria Eliney , Menezes Nei Soares , Ferrari Renata Spagnoli , Banks Rosamonde E. , Vasudev Naveen S. , Zaridze David , Mukeriya Anush , Shangina Oxana , Matveev Vsevolod , Foretova Lenka , Navratilova Marie , Holcatova Ivana , Hornakova Anna , Janout Vladimir , Purdue Mark , Rothman Nathaniel , Chanock Stephen J. , Ueland Per Magne , Johansson Mattias , McKay James , Scelo Ghislaine , Chanudet Estelle , Humphreys Laura , de Carvalho Ana Carolina , Perdomo Sandra , Alexandrov Ludmil B. , Stratton Michael R. , Brennan Paul 
Published: June 2023

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not been identified by conventional epidemiology yet potentially make a substantial contribution to cancer burden1. This pertains to clear cell renal cell carcinoma (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence2. Some carcinogens generate somatic mutations and a complementary strategy for detecting past exposures is to sequence the genomes of cancers from populations with different incidence rates and infer underlying causes from differences in patterns of somatic mutations. Here, we sequenced 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. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher kidney cancer incidence rates (p-value <6 × 10−18). 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, geographically variable, mutagenic exposures potentially affecting 10s of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.