Geographic variation of mutagenic exposures in kidney cancer genomes

Author:

Senkin SergeyORCID,Moody SarahORCID,Díaz-Gay MarcosORCID,Abedi-Ardekani Behnoush,Cattiaux ThomasORCID,Ferreiro-Iglesias Aida,Wang JingweiORCID,Fitzgerald StephenORCID,Kazachkova Mariya,Vangara Raviteja,Le Anh PhuongORCID,Bergstrom Erik N.,Khandekar Azhar,Otlu Burçak,Cheema SaaminORCID,Latimer Calli,Thomas Emily,Atkins Joshua Ronald,Smith-Byrne KarlORCID,Cortez Cardoso Penha Ricardo,Carreira Christine,Chopard Priscilia,Gaborieau Valérie,Keski-Rahkonen PekkaORCID,Jones DavidORCID,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 SlavisaORCID,Milosavljevic Sasa,Bartlett John M. S.,Albert Monique,Phouthavongsy LarryORCID,Ashton-Prolla Patricia,Botton Mariana R.ORCID,Silva Neto Brasil,Bezerra Stephania Martins,Curado Maria Paula,Zequi Stênio de CássioORCID,Reis Rui Manuel,Faria Eliney Ferreira,de Menezes Nei Soares,Ferrari Renata Spagnoli,Banks Rosamonde E.ORCID,Vasudev Naveen S.,Zaridze David,Mukeriya Anush,Shangina Oxana,Matveev VsevolodORCID,Foretova LenkaORCID,Navratilova Marie,Holcatova Ivana,Hornakova AnnaORCID,Janout Vladimir,Purdue Mark P.,Rothman Nathaniel,Chanock Stephen J.ORCID,Ueland Per Magne,Johansson Mattias,McKay James,Scelo Ghislaine,Chanudet Estelle,Humphreys Laura,de Carvalho Ana Carolina,Perdomo Sandra,Alexandrov Ludmil B.ORCID,Stratton Michael R.ORCID,Brennan PaulORCID

Abstract

AbstractInternational 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.

Publisher

Springer Science and Business Media LLC

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