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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. Furthermore, 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.

Authors:
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Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1341860
Report Number(s):
LA-UR-16-21897
Journal ID: ISSN 1061-4036
Grant/Contract Number:
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Genetics
Additional Journal Information:
Journal Volume: 49; Journal Issue: 3; Journal ID: ISSN 1061-4036
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Biological Science

Citation Formats

Glodzik, Dominik, Morganella, Sandro, Davies, Helen, Simpson, Peter T., Li, Yilong, Zou, Xueqing, Diez-Perez, Javier, Staaf, Johan, Alexandrov, Ludmil B., Smid, Marcel, Brinkman, Arie B., Rye, Inga Hansine, Russnes, Hege, Raine, Keiran, Purdie, Colin A., Lakhani, Sunil R., Thompson, Alastair M., Birney, Ewan, Stunnenberg, Hendrik G., van de Vijver, Marc J., Martens, John W. M., Børresen-Dale, Anne-Lise, Richardson, Andrea L., Kong, Gu, Viari, Alain, Easton, Douglas, Evan, Gerard, Campbell, Peter J., Stratton, Michael R., and Nik-Zainal, Serena. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. United States: N. p., 2017. Web. doi:10.1038/ng.3771.
Glodzik, Dominik, Morganella, Sandro, Davies, Helen, Simpson, Peter T., Li, Yilong, Zou, Xueqing, Diez-Perez, Javier, Staaf, Johan, Alexandrov, Ludmil B., Smid, Marcel, Brinkman, Arie B., Rye, Inga Hansine, Russnes, Hege, Raine, Keiran, Purdie, Colin A., Lakhani, Sunil R., Thompson, Alastair M., Birney, Ewan, Stunnenberg, Hendrik G., van de Vijver, Marc J., Martens, John W. M., Børresen-Dale, Anne-Lise, Richardson, Andrea L., Kong, Gu, Viari, Alain, Easton, Douglas, Evan, Gerard, Campbell, Peter J., Stratton, Michael R., & Nik-Zainal, Serena. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. United States. doi:10.1038/ng.3771.
Glodzik, Dominik, Morganella, Sandro, Davies, Helen, Simpson, Peter T., Li, Yilong, Zou, Xueqing, Diez-Perez, Javier, Staaf, Johan, Alexandrov, Ludmil B., Smid, Marcel, Brinkman, Arie B., Rye, Inga Hansine, Russnes, Hege, Raine, Keiran, Purdie, Colin A., Lakhani, Sunil R., Thompson, Alastair M., Birney, Ewan, Stunnenberg, Hendrik G., van de Vijver, Marc J., Martens, John W. M., Børresen-Dale, Anne-Lise, Richardson, Andrea L., Kong, Gu, Viari, Alain, Easton, Douglas, Evan, Gerard, Campbell, Peter J., Stratton, Michael R., and Nik-Zainal, Serena. Mon . "A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers". United States. doi:10.1038/ng.3771. https://www.osti.gov/servlets/purl/1341860.
@article{osti_1341860,
title = {A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers},
author = {Glodzik, Dominik and Morganella, Sandro and Davies, Helen and Simpson, Peter T. and Li, Yilong and Zou, Xueqing and Diez-Perez, Javier and Staaf, Johan and Alexandrov, Ludmil B. and Smid, Marcel and Brinkman, Arie B. and Rye, Inga Hansine and Russnes, Hege and Raine, Keiran and Purdie, Colin A. and Lakhani, Sunil R. and Thompson, Alastair M. and Birney, Ewan 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 Viari, Alain and Easton, Douglas and Evan, Gerard and Campbell, Peter J. and Stratton, Michael R. and Nik-Zainal, Serena},
abstractNote = {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. Furthermore, 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.},
doi = {10.1038/ng.3771},
journal = {Nature Genetics},
number = 3,
volume = 49,
place = {United States},
year = {Mon Jan 23 00:00:00 EST 2017},
month = {Mon Jan 23 00:00:00 EST 2017}
}

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