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Title: Mutational signatures associated with tobacco smoking in human cancer

Tobacco smoking increases the risk of at least 17 classes of cancer. Here, we analyzed somatic mutations and DNA methylation in 5,243 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 edi ting by APOBEC cytidine deaminases and of an endogenous clock-like 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.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ;  [8] ;  [9] ;  [10] ;  [11] ;  [12] ;  [13] ;  [5]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Center for Nonlinear Studies, Theoretical Biology and Biophysics; Univ. of New Mexico Comprehensive Cancer Center, Albuquerque, NM (United States)
  2. Korea Advanced Inst. Science and Technology (KAIST), Daejeon (Korea, Republic of). Graduate School of Medical Science and Engineering (GSMSE)
  3. Francis Crick Inst., London (United Kingdom)
  4. Francis Crick Inst., London (United Kingdom). Human Genome Lab., Dept. of Human Genetics
  5. Wellcome Trust Sanger Inst., Cambridge (United Kingdom)
  6. Wellcome Trust Sanger Inst., Cambridge (United Kingdom); Addenbrooke's Hospital National Health Service (NHS), Cambridge (United Kingdom). Dept. of Medical Genetics
  7. National Cancer Center Research Inst., Tokyo (Japan). Division of Cancer Genomics
  8. RIKEN Center for Integrative Medical Sciences, Tokyo (Japan). Lab. for Genome Sequencing Analysis; Kyoto Univ. (Japan). Graduate School of Medicine, Dept. of Drug Discovery Medicine
  9. RIKEN Center for Integrative Medical Sciences, Tokyo (Japan). Lab. for Genome Sequencing Analysis
  10. National Cancer Center Research Inst., Tokyo (Japan). Division of Cancer Genomics; Univ. of Tokyo (Japan). Lab. of Molecular Medicine, Human Genome Center, Inst. of Medical Science
  11. Wellcome Trust Sanger Inst., Cambridge (United Kingdom); Univ. of Cambridge (United Kingdom). Dept. of Haematology
  12. Human Genetics Foundation (HuGeF), Torino (Italy); Imperial College, London (United Kingdom). School of Public Health, MRC-PHE Centre for Environment and Health, Dept. of Epidemiology and Biostatistics
  13. King's College London (United Kingdom). MRC-PHE Centre for Environment and Health, Analytical and Environmental Sciences Division
Publication Date:
Report Number(s):
LA-UR-16-23165
Journal ID: ISSN 0036-8075
Grant/Contract Number:
AC52-06NA25396; 098051; WT100183MA; 15ck0106094h0002; 308610-FP7; 101126/Z/13/Z; 101126/B/13/Z; WT088340MA; FC001202; C313/A14329; 02
Type:
Published Article
Journal Name:
Science
Additional Journal Information:
Journal Volume: 354; Journal Issue: 6312; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE National Nuclear Security Administration (NNSA); Wellcome Trust; European Commission (EC)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Biological Science
OSTI Identifier:
1347826
Alternate Identifier(s):
OSTI ID: 1340930