Mutational signatures associated with tobacco smoking in human cancer

Author:

Alexandrov Ludmil B.123,Ju Young Seok4,Haase Kerstin5,Van Loo Peter56,Martincorena Iñigo7,Nik-Zainal Serena78,Totoki Yasushi9,Fujimoto Akihiro1011,Nakagawa Hidewaki10,Shibata Tatsuhiro912,Campbell Peter J.713,Vineis Paolo1415,Phillips David H.16,Stratton Michael R.7

Affiliation:

1. Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, USA.

2. Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.

3. University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87102, USA.

4. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.

5. The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.

6. Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.

7. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.

8. Department of Medical Genetics, Addenbrooke’s Hospital National Health Service Trust, Cambridge, UK.

9. Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

10. Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

11. Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

12. Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.

13. Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.

14. Human Genetics Foundation, 10126 Torino, Italy.

15. Department of Epidemiology and Biostatistics, Medical Research Council (MRC)–Public Health England (PHE) Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.

16. King’s College London, MRC-PHE Centre for Environment and Health, Analytical and Environmental Sciences Division, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.

Abstract

Assessing smoke damage in cancer genomes We have known for over 60 years that smoking tobacco is one of the most avoidable risk factors for cancer. Yet the detailed mechanisms by which tobacco smoke damages the genome and creates the mutations that ultimately cause cancer are still not fully understood. Alexandrov et al. examined mutational signatures and DNA methylation changes in over 5000 genome sequences from 17 different cancer types linked to smoking (see the Perspective by Pfeifer). They found a complex pattern of mutational signatures. Only cancers originating in tissues directly exposed to smoke showed a signature characteristic of the known tobacco carcinogen benzo[ a ]pyrene. One mysterious signature was shared by all smoking-associated cancers but is of unknown origin. Smoking had only a modest effect on DNA methylation. Science , this issue p. 618 ; see also p. 549

Funder

Wellcome Trust Intermediate Fellowship

Wellcome Trust Senior Clinical Research Fellowship

U.S. Department of Energy (DOE) National Nuclear Security Administration

Francis Crick Institute

UK MRC

Cancer Research UK

Wellcome Trust

National Institute for Health Research (NIHR)

EXPOSOMICS

Japan Agency for Medical Research and Development

National Cancer Center Research and Development Funds

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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