The topography of mutational processes in breast cancer genomes.
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Authors
Morganella, Sandro
Alexandrov, Ludmil B
Glodzik, Dominik
Zou, Xueqing
Davies, Helen
Staaf, Johan
Sieuwerts, Anieta M
Brinkman, Arie B
Martin, Sancha
Ramakrishna, Manasa
Butler, Adam
Kim, Hyung-Yong
Borg, Åke
Sotiriou, Christos
Futreal, P Andrew
Campbell, Peter J
Van Laere, Steven
Eyfjord, Jorunn E
Thompson, Alastair M
Stunnenberg, Hendrik G
van de Vijver, Marc J
Martens, John WM
Børresen-Dale, Anne-Lise
Richardson, Andrea L
Kong, Gu
Thomas, Gilles
Sale, Julian
Stratton, Michael R
Birney, Ewan
Nik-Zainal, Serena
Publication Date
2016-05-02Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
7
Pages
11383
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
Morganella, S., Alexandrov, L. B., Glodzik, D., Zou, X., Davies, H., Staaf, J., Sieuwerts, A. M., et al. (2016). The topography of mutational processes in breast cancer genomes.. Nat Commun, 7 11383. https://doi.org/10.1038/ncomms11383
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 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.
Keywords
Chromatin, Humans, Breast Neoplasms, DNA Damage, Apolipoproteins B, Sequence Analysis, DNA, DNA Repair, DNA Replication, Transcription, Genetic, Mutagenesis, Mutation, Genome, Human, Female, MCF-7 Cells
Sponsorship
European Commission (242006)
Identifiers
External DOI: https://doi.org/10.1038/ncomms11383
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284500
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