Geographic variation of mutagenic exposures in kidney cancer genomes

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 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 Carvalho, Sandra Perdomo, Ludmil B. Alexandrov, Michael R. Stratton and Paul Brennan ()
Additional contact information
Sergey Senkin: International Agency for Research on Cancer (IARC/WHO)
Sarah Moody: Wellcome Sanger Institute
Marcos Díaz-Gay: University of California San Diego
Behnoush Abedi-Ardekani: International Agency for Research on Cancer (IARC/WHO)
Thomas Cattiaux: International Agency for Research on Cancer (IARC/WHO)
Aida Ferreiro-Iglesias: International Agency for Research on Cancer (IARC/WHO)
Jingwei Wang: Wellcome Sanger Institute
Stephen Fitzgerald: Wellcome Sanger Institute
Mariya Kazachkova: University of California San Diego
Raviteja Vangara: University of California San Diego
Anh Phuong Le: Wellcome Sanger Institute
Erik N. Bergstrom: University of California San Diego
Azhar Khandekar: University of California San Diego
Burçak Otlu: University of California San Diego
Saamin Cheema: Wellcome Sanger Institute
Calli Latimer: Wellcome Sanger Institute
Emily Thomas: Wellcome Sanger Institute
Joshua Ronald Atkins: University of Oxford
Karl Smith-Byrne: University of Oxford
Ricardo Cortez Cardoso Penha: International Agency for Research on Cancer (IARC/WHO)
Christine Carreira: International Agency for Research on Cancer (IARC/WHO)
Priscilia Chopard: International Agency for Research on Cancer (IARC/WHO)
Valérie Gaborieau: International Agency for Research on Cancer (IARC/WHO)
Pekka Keski-Rahkonen: International Agency for Research on Cancer (IARC/WHO)
David Jones: Wellcome Sanger Institute
Jon W. Teague: Wellcome Sanger Institute
Sophie Ferlicot: Univeristé Paris-Saclay
Mojgan Asgari: Iran University of Medical Sciences
Surasak Sangkhathat: Prince of Songkla University
Worapat Attawettayanon: Prince of Songkla University
Beata Świątkowska: Nofer Institute of Occupational Medicine
Sonata Jarmalaite: National Cancer Institute
Rasa Sabaliauskaite: National Cancer Institute
Tatsuhiro Shibata: The University of Tokyo
Akihiko Fukagawa: National Cancer Center Research Institute
Dana Mates: National Institute of Public Health
Viorel Jinga: Carol Davila University of Medicine and Pharmacy, Prof. Dr. Th. Burghele Clinical Hospital
Stefan Rascu: Carol Davila University of Medicine and Pharmacy, Prof. Dr. Th. Burghele Clinical Hospital
Mirjana Mijuskovic: Military Medical Academy
Slavisa Savic: University Hospital Dr D. Misovic Clinical Center
Sasa Milosavljevic: International Organization for Cancer Prevention and Research
John M. S. Bartlett: University of Edinburgh
Monique Albert: University of Guelph
Larry Phouthavongsy: Ontario Institute for Cancer Research
Patricia Ashton-Prolla: Hospital de Clínicas de Porto Alegre
Mariana R. Botton: Hospital de Clínicas de Porto Alegre
Brasil Silva Neto: Hospital de Clínicas de Porto Alegre
Stephania Martins Bezerra: A. C. Camargo Cancer Center
Maria Paula Curado: A. C. Camargo Cancer Center
Stênio de Cássio Zequi: A. C. Camargo Cancer Center
Rui Manuel Reis: Barretos Cancer Hospital
Eliney Ferreira Faria: Faculdade Ciências Médicas de Minas Gerais
Nei Soares Menezes: Barretos Cancer Hospital
Renata Spagnoli Ferrari: Barretos Cancer Hospital
Rosamonde E. Banks: University of Leeds
Naveen S. Vasudev: University of Leeds
David Zaridze: N. N. Blokhin National Medical Research Centre of Oncology
Anush Mukeriya: N. N. Blokhin National Medical Research Centre of Oncology
Oxana Shangina: N. N. Blokhin National Medical Research Centre of Oncology
Vsevolod Matveev: N. N. Blokhin National Medical Research Centre of Oncology
Lenka Foretova: Masaryk Memorial Cancer Institute
Marie Navratilova: Masaryk Memorial Cancer Institute
Ivana Holcatova: Charles University
Anna Hornakova: Charles University
Vladimir Janout: Palacky University
Mark P. Purdue: National Cancer Institute
Nathaniel Rothman: National Cancer Institute
Stephen J. Chanock: National Cancer Institute
Per Magne Ueland: Bevital AS
Mattias Johansson: International Agency for Research on Cancer (IARC/WHO)
James McKay: International Agency for Research on Cancer (IARC/WHO)
Ghislaine Scelo: Observational and Pragmatic Research Institute Pte Ltd
Estelle Chanudet: Radboud University Medical Centre
Laura Humphreys: Wellcome Sanger Institute
Ana Carolina Carvalho: International Agency for Research on Cancer (IARC/WHO)
Sandra Perdomo: International Agency for Research on Cancer (IARC/WHO)
Ludmil B. Alexandrov: University of California San Diego
Michael R. Stratton: Wellcome Sanger Institute
Paul Brennan: International Agency for Research on Cancer (IARC/WHO)

Nature, 2024, vol. 629, issue 8013, 910-918

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07368-2

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