Geographic variation of mutagenic exposures in kidney cancer genomes

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures not yet identified by conventional epidemiology. In clear cell renal cell carcinoma (ccRCC), obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in incidence. Underlying causes can be inferred by sequencing cancer genomes from populations with different incidence rates and detecting differences in somatic mutation patterns. We sequenced 962 ccRCCs from 11 countries with varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases but were rare elsewhere. In Japan, a mutational signature of unknown cause (SBS12) was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause (SBS40b) was ubiquitous but showed higher mutation loads in countries with higher ccRCC incidence. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting non-mutagenic mechanisms underlie these risk factors. These findings indicate multiple, geographically variable mutagenic exposures that potentially affect tens of millions of people and showcase opportunities for new insights into cancer causation through large-scale global cancer genomics.

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