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The topography of mutational processes in breast cancer genomes

Morganella, Sandro; Alexandrov, Ludmil B.; Glodzik, Dominik; Zou, Xueqing; Davies, Helen; Staaf, Johan LU ; Sieuwerts, Anieta M.; Brinkman, Arie B.; Martin, Sancha and Ramakrishna, Manasa, et al. (2016) In Nature Communications 7.
Abstract

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... (More)

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. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

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@misc{ab43a332-5aec-4446-bde6-09b9546317f5,
  abstract     = {<p>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. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.</p>},
  author       = {Morganella, Sandro and Alexandrov, Ludmil B. and Glodzik, Dominik and Zou, Xueqing and Davies, Helen and Staaf, Johan and Sieuwerts, Anieta M. and Brinkman, Arie B. and Martin, Sancha and Ramakrishna, Manasa and Butler, Adam and Kim, Hyung Yong and Borg, Åke and Sotiriou, Christos and Futreal, P. Andrew and Campbell, Peter J. and Span, Paul N. and Van Laere, Steven and Lakhani, Sunil R. and Eyfjord, Jorunn E. and Thompson, Alastair M. and Stunnenberg, Hendrik G. and Van De Vijver, Marc J. and Martens, John W M and Børresen-Dale, Anne Lise and Richardson, Andrea L. and Kong, Gu and Thomas, Gilles and Sale, Julian and Rada, Cristina and Stratton, Michael R. and Birney, Ewan and Nik-Zainal, Serena},
  issn         = {2041-1723},
  language     = {eng},
  month        = {05},
  publisher    = {ARRAY(0x8107268)},
  series       = {Nature Communications},
  title        = {The topography of mutational processes in breast cancer genomes},
  url          = {http://dx.doi.org/10.1038/ncomms11383},
  volume       = {7},
  year         = {2016},
}