The topography of mutational processes in breast cancer genomes

Sandro Morganella; Ludmil B. Alexandrov; Dominik Glodzik; Xueqing Zou; Helen Davies; Johan Staaf; Anieta M. Sieuwerts; Arie B. Brinkman; Sancha Martin; Manasa Ramakrishna; Adam Butler; Hyung-Yong Kim; Åke Borg; Christos Sotiriou; P. Andrew Futreal; Peter J. Campbell; Paul N. Span; Steven van Laere; Sunil R. Lakhani; Jorunn E. Eyfjord; Alastair M. Thompson; Hendrik G. Stunnenberg; Marc J. van de Vijver; John W. M. Martens; Anne-Lise Børresen-Dale; Andrea L. Richardson; Gu Kong; Gilles Thomas; Julian Sale; Cristina Rada; Michael R. Stratton; Ewan Birney; Serena Nik-Zainal

doi:https://doi.org/10.1038/ncomms11383

The topography of mutational processes in breast cancer genomes

Sandro Morganella, Ludmil B. Alexandrov, Dominik Glodzik, Xueqing Zou, Helen Davies, Johan Staaf, Anieta M. Sieuwerts, Arie B. Brinkman, Sancha Martin, Manasa Ramakrishna, Adam Butler, Hyung-Yong Kim, Åke Borg, Christos Sotiriou, P. Andrew Futreal, Peter J. Campbell, Paul N. Span, Steven van Laere, Sunil R. Lakhani, Jorunn E. EyfjordAlastair M. Thompson, Hendrik G. Stunnenberg, Marc J. van de Vijver, John W. M. Martens, Anne-Lise Børresen-Dale, Andrea L. Richardson, Gu Kong, Gilles Thomas, Julian Sale, Cristina Rada, Michael R. Stratton, Ewan Birney, Serena Nik-Zainal

Research output: Contribution to journal › Article › Academic › peer-review

197 Citations (Scopus)

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

Original language	English
Pages (from-to)	11383
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11383
Publication status	Published - 2016

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https://doi.org/10.1038/ncomms11383

Cite this

Morganella, S., Alexandrov, L. B., Glodzik, D., Zou, X., Davies, H., Staaf, J., Sieuwerts, A. M., Brinkman, A. B., Martin, S., Ramakrishna, M., Butler, A., Kim, H.-Y., Borg, Å., Sotiriou, C., Futreal, P. A., Campbell, P. J., Span, P. N., van Laere, S., Lakhani, S. R., ... Nik-Zainal, S. (2016). The topography of mutational processes in breast cancer genomes. Nature communications, 7, 11383. https://doi.org/10.1038/ncomms11383

@article{e83feb48928b49898dd5f43967f3ae40,

title = "The topography of mutational processes in breast cancer genomes",

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",

author = "Sandro Morganella and Alexandrov, {Ludmil B.} and Dominik Glodzik and Xueqing Zou and Helen Davies and Johan Staaf and Sieuwerts, {Anieta M.} and Brinkman, {Arie B.} and Sancha Martin and Manasa Ramakrishna and Adam Butler and Hyung-Yong Kim and {\AA}ke Borg and Christos Sotiriou 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 Anne-Lise B{\o}rresen-Dale and Richardson, {Andrea L.} and Gu Kong and Gilles Thomas and Julian Sale and Cristina Rada and Stratton, {Michael R.} and Ewan Birney and Serena Nik-Zainal",

year = "2016",

doi = "https://doi.org/10.1038/ncomms11383",

language = "English",

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pages = "11383",

journal = "Nature communications",

issn = "2041-1723",

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Morganella, S, Alexandrov, LB, Glodzik, D, Zou, X, Davies, H, Staaf, J, Sieuwerts, AM, Brinkman, AB, Martin, S, Ramakrishna, M, Butler, A, Kim, H-Y, Borg, Å, Sotiriou, C, Futreal, PA, Campbell, PJ, Span, PN, van Laere, S, Lakhani, SR, Eyfjord, JE, Thompson, AM, Stunnenberg, HG, van de Vijver, MJ, Martens, JWM, Børresen-Dale, A-L, Richardson, AL, Kong, G, Thomas, G, Sale, J, Rada, C, Stratton, MR, Birney, E & Nik-Zainal, S 2016, 'The topography of mutational processes in breast cancer genomes', Nature communications, vol. 7, pp. 11383. https://doi.org/10.1038/ncomms11383

TY - JOUR

T1 - The topography of mutational processes in breast cancer genomes

AU - Morganella, Sandro

AU - Alexandrov, Ludmil B.

AU - Glodzik, Dominik

AU - Zou, Xueqing

AU - Davies, Helen

AU - Staaf, Johan

AU - Sieuwerts, Anieta M.

AU - Brinkman, Arie B.

AU - Martin, Sancha

AU - Ramakrishna, Manasa

AU - Butler, Adam

AU - Kim, Hyung-Yong

AU - Borg, Åke

AU - Sotiriou, Christos

AU - Futreal, P. Andrew

AU - Campbell, Peter J.

AU - Span, Paul N.

AU - van Laere, Steven

AU - Lakhani, Sunil R.

AU - Eyfjord, Jorunn E.

AU - Thompson, Alastair M.

AU - Stunnenberg, Hendrik G.

AU - van de Vijver, Marc J.

AU - Martens, John W. M.

AU - Børresen-Dale, Anne-Lise

AU - Richardson, Andrea L.

AU - Kong, Gu

AU - Thomas, Gilles

AU - Sale, Julian

AU - Rada, Cristina

AU - Stratton, Michael R.

AU - Birney, Ewan

AU - Nik-Zainal, Serena

PY - 2016

Y1 - 2016

N2 - 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

AB - 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

U2 - https://doi.org/10.1038/ncomms11383

DO - https://doi.org/10.1038/ncomms11383

M3 - Article

C2 - 27136393

SN - 2041-1723

VL - 7

SP - 11383

JO - Nature communications

JF - Nature communications

ER -