A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Dominik Glodzik; Sandro Morganella; Helen Davies; Peter T Simpson; Yilong Li; Xueqing Zou; Javier Diez-Perez; Johan Staaf; Ludmil B Alexandrov; Marcel Smid; Arie B Brinkman; Inga Hansine Rye; Hege Russnes; Keiran Raine; Colin A Purdie; Sunil R Lakhani; Alastair M Thompson; Ewan Birney; Hendrik G Stunnenberg; Marc J van de Vijver; John W M Martens; Anne-Lise Børresen-Dale; Andrea L Richardson; Gu Kong; Alain Viari; Douglas Easton; Gerard Evan; Peter J Campbell; Michael R Stratton; Serena Nik-Zainal

doi:10.1038/ng.3771

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Dominik Glodzik, Sandro Morganella, Helen Davies, Peter T Simpson, Yilong Li, Xueqing Zou, Javier Diez-Perez, Johan Staaf, Ludmil B Alexandrov, Marcel Smid, Arie B Brinkman, Inga Hansine Rye, Hege Russnes, Keiran Raine, Colin A Purdie, Sunil R Lakhani, Alastair M Thompson, Ewan Birney, Hendrik G Stunnenberg, Marc J van de VijverJohn W M Martens, Anne-Lise Børresen-Dale, Andrea L Richardson, Gu Kong, Alain Viari, Douglas Easton, Gerard Evan, Peter J Campbell, Michael R Stratton, Serena Nik-Zainal (Lead / Corresponding author)

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

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Abstract

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.

Original language	English
Pages (from-to)	341-348
Number of pages	11
Journal	Nature Genetics
Volume	49
Issue number	3
Early online date	23 Jan 2017
DOIs	https://doi.org/10.1038/ng.3771
Publication status	Published - Mar 2017

Keywords

Breast cancer
Genetics research
Genomics

UN SDGs

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

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10.1038/ng.3771

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Glodzik, D., Morganella, S., Davies, H., Simpson, P. T., Li, Y., Zou, X., Diez-Perez, J., Staaf, J., Alexandrov, L. B., Smid, M., Brinkman, A. B., Rye, I. H., Russnes, H., Raine, K., Purdie, C. A., Lakhani, S. R., Thompson, A. M., Birney, E., Stunnenberg, H. G., ... Nik-Zainal, S. (2017). A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nature Genetics, 49(3), 341-348. https://doi.org/10.1038/ng.3771

@article{e8e5edf389524206a7b70f3274c0f358,

title = "A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers",

abstract = "Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.",

keywords = "Breast cancer , Genetics research , Genomics ",

author = "Dominik Glodzik and Sandro Morganella and Helen Davies and Simpson, {Peter T} and Yilong Li and Xueqing Zou and Javier Diez-Perez and Johan Staaf and Alexandrov, {Ludmil B} and Marcel Smid and Brinkman, {Arie B} and Rye, {Inga Hansine} and Hege Russnes and Keiran Raine and Purdie, {Colin A} and Lakhani, {Sunil R} and Thompson, {Alastair M} and Ewan Birney 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 Alain Viari and Douglas Easton and Gerard Evan and Campbell, {Peter J} and Stratton, {Michael R} and Serena Nik-Zainal",

note = "Data used in this analysis were funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community's Seventh Framework Programme (FP7/2010-2014) under grant agreement number 242006; the Triple Negative project, funded by the Wellcome Trust (grant reference 077012/Z/05/Z); and the HER2+ project, funded by Institut National du Cancer (INCa) in France (grant nos. 226-2009, 02-2011, 41-2012, 144-2008 and 06-2012). J.W.M.M. received funding for this project through an ERC Advanced grant (no. 322737). G.K. is supported by National Research Foundation of Korea grants (NRF 2015R1A2A1A10052578). The ICGC Asian Breast Cancer Project was funded through a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111218-SC01). D.G. is supported by the EU-FP7-SUPPRESSTEM project. S.N.-Z. is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is supported as a Wellcome Beit Fellow.",

year = "2017",

month = mar,

doi = "10.1038/ng.3771",

language = "English",

volume = "49",

pages = "341--348",

journal = "Nature Genetics",

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Glodzik, D, Morganella, S, Davies, H, Simpson, PT, Li, Y, Zou, X, Diez-Perez, J, Staaf, J, Alexandrov, LB, Smid, M, Brinkman, AB, Rye, IH, Russnes, H, Raine, K, Purdie, CA, Lakhani, SR, Thompson, AM, Birney, E, Stunnenberg, HG, van de Vijver, MJ, Martens, JWM, Børresen-Dale, A-L, Richardson, AL, Kong, G, Viari, A, Easton, D, Evan, G, Campbell, PJ, Stratton, MR & Nik-Zainal, S 2017, 'A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers', Nature Genetics, vol. 49, no. 3, pp. 341-348. https://doi.org/10.1038/ng.3771

TY - JOUR

T1 - A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

AU - Glodzik, Dominik

AU - Morganella, Sandro

AU - Davies, Helen

AU - Simpson, Peter T

AU - Li, Yilong

AU - Zou, Xueqing

AU - Diez-Perez, Javier

AU - Staaf, Johan

AU - Alexandrov, Ludmil B

AU - Smid, Marcel

AU - Brinkman, Arie B

AU - Rye, Inga Hansine

AU - Russnes, Hege

AU - Raine, Keiran

AU - Purdie, Colin A

AU - Lakhani, Sunil R

AU - Thompson, Alastair M

AU - Birney, Ewan

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 - Viari, Alain

AU - Easton, Douglas

AU - Evan, Gerard

AU - Campbell, Peter J

AU - Stratton, Michael R

AU - Nik-Zainal, Serena

N1 - Data used in this analysis were funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community's Seventh Framework Programme (FP7/2010-2014) under grant agreement number 242006; the Triple Negative project, funded by the Wellcome Trust (grant reference 077012/Z/05/Z); and the HER2+ project, funded by Institut National du Cancer (INCa) in France (grant nos. 226-2009, 02-2011, 41-2012, 144-2008 and 06-2012). J.W.M.M. received funding for this project through an ERC Advanced grant (no. 322737). G.K. is supported by National Research Foundation of Korea grants (NRF 2015R1A2A1A10052578). The ICGC Asian Breast Cancer Project was funded through a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111218-SC01). D.G. is supported by the EU-FP7-SUPPRESSTEM project. S.N.-Z. is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is supported as a Wellcome Beit Fellow.

PY - 2017/3

Y1 - 2017/3

N2 - Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.

AB - Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.

KW - Breast cancer

KW - Genetics research

KW - Genomics

U2 - 10.1038/ng.3771

DO - 10.1038/ng.3771

M3 - Article

C2 - 28112740

SN - 1061-4036

VL - 49

SP - 341

EP - 348

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Abstract

Keywords

UN SDGs

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