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 , Cortez Cardoso Penha Ricardo , 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. , Silva Neto Brasil , Bezerra Stephania Martins , Curado Maria Paula , Zequi Stênio de Cássio , Reis Rui Manuel , Faria Eliney Ferreira , de 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 P. , 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: May 2024

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.