Mutational signatures associated with tobacco smoking in human cancer.
Tobacco smoking increases the risk of at least 17 classes of human cancer. We analyzed somatic mutations and DNA methylation in 5243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clocklike mutational process. Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.
Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, USA. lba@lanl.gov mrs@sanger.ac.uk.|Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.|University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87102, USA.
Ludmil B
LB
Alexandrov
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
Young Seok
YS
Ju
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Kerstin
K
Haase
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.|Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
Peter
P
Van Loo
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
Iñigo
I
Martincorena
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.|Department of Medical Genetics, Addenbrooke's Hospital National Health Service Trust, Cambridge, UK.
Serena
S
Nik-Zainal
Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Yasushi
Y
Totoki
Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.|Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Akihiro
A
Fujimoto
Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Hidewaki
H
Nakagawa
Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.|Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
Tatsuhiro
T
Shibata
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.|Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
Peter J
PJ
Campbell
Human Genetics Foundation, 10126 Torino, Italy.|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.
Paolo
P
Vineis
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.
David H
DH
Phillips
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK. lba@lanl.gov mrs@sanger.ac.uk.
Michael R
MR
Stratton
D000071478:APOBEC Deaminases / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D018899:CpG Islands; D004249:DNA Damage; D019175:DNA Methylation; D059472:Exome / Q000235:genetics; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D012306:Risk; D012907:Smoking / Q000453:epidemiology / Q000235:genetics*; D014026:Nicotiana
D002273:Carcinogens; D000071478:APOBEC Deaminases