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This content will become publicly available on January 1, 2017

Title: The topography of mutational processes in breast cancer genomes

Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Lastly, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.
 [1] ;  [2] ;  [3] ;  [3] ;  [3] ;  [4] ;  [5] ;  [6] ;  [3] ;  [3] ;  [3] ;  [7] ;  [4] ;  [8] ;  [9] ;  [3] ;  [10] ;  [11] ;  [12] ;  [13] more »;  [14] ;  [6] ;  [15] ;  [5] ;  [16] ;  [17] ;  [7] ;  [18] ;  [19] ;  [19] ;  [3] ;  [1] ;  [20] « less
  1. European Bioinformatics Institute, Cambridgeshire (United Kingdom)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Wellcome Trust Sanger Institute, Cambridge (United Kingdom)
  3. Wellcome Trust Sanger Institute, Cambridge (United Kingdom)
  4. Lund Univ., Lund (Sweden)
  5. Erasmus Univ. Medical Center, Rotterdam (The Netherlands)
  6. Radboud Univ., Nijmegen (The Netherlands)
  7. Hanyang Univ., Seoul (South Korea)
  8. Univ. Libre de Bruxelles, Brussels (Belgium)
  9. European Bioinformatics Institute, Cambridgeshire (United Kingdom); UT MD Anderson Cancer Center, Houston, TX (United States)
  10. Radboud Univ. Medical Center, Nijmegen (The Netherlands)
  11. Univ. of Antwerp, Antwerp (Belgium)
  12. Univ. of Queensland, Queensland (Australia); The Royal Brisbane and Women's Hospital, Queensland (Australia)
  13. Univ. of Iceland (Iceland)
  14. Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States); Univ. of Dundee, Dundee (United Kingdom)
  15. Academic Medical Center, Amsterdam (The Netherlands)
  16. Oslo Univ. Hospital, The Norwegian Radium Hospital, Oslo (Norway); Univ. of Oslo, Oslo (Norway)
  17. Brigham and Women's Hospital, Boston, MA (United States); Dana-Farber Cancer Institute, Boston, MA (United States)
  18. Centre Leon Berard, Lyon Cedex (France)
  19. MRC Lab. of Molecular Biology, Cambridge (United Kingdom)
  20. Wellcome Trust Sanger Institute, Cambridge (United Kingdom); Cambridge Univ. Hospitals NHS Foundation Trust, Cambridge (United Kingdom)
Publication Date:
OSTI Identifier:
Report Number(s):
Journal ID: ISSN 2041-1723
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2041-1723
Nature Publishing Group
Research Org:
Los Alamos National Laboratory (LANL)
Sponsoring Org:
Country of Publication:
United States