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: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

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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
Article number	11383
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11383
Publication status	Published - 2 May 2016

Keywords

Biological sciences
Cancer
Genetics
Molecular biology

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology
General Chemistry
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, Article 11383. https://doi.org/10.1038/ncomms11383

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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.",

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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, HY, 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, AL, 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, 11383. https://doi.org/10.1038/ncomms11383

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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 - 2016/5/2

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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.

KW - Biological sciences

KW - Cancer

KW - Genetics

KW - Molecular biology

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DO - 10.1038/ncomms11383

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SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11383

ER -

The topography of mutational processes in breast cancer genomes

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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