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

Glodzik, Dominik LU ; Morganella, Sandro; Davies, Helen R.; Simpson, Peter T; Li, Yilong; Zou, Xueqing; Diez-Perez, Javier; Staaf, Johan LU ; Alexandrov, Ludmil B. and Smid, Marcel, et al. (2017) In Nature Genetics 49(3). p.341-348
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... (More)

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.

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Nature Genetics
volume
49
issue
3
pages
8 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85010840152
  • wos:000394917800007
ISSN
1061-4036
DOI
10.1038/ng.3771
language
English
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yes
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dee3611f-7ac5-404e-89d8-f6c6eaf30607
date added to LUP
2017-03-13 09:59:51
date last changed
2018-05-13 04:29:42
@article{dee3611f-7ac5-404e-89d8-f6c6eaf30607,
  abstract     = {<p>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 (&gt;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.</p>},
  author       = {Glodzik, Dominik and Morganella, Sandro and Davies, Helen R. 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},
  issn         = {1061-4036},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {341--348},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers},
  url          = {http://dx.doi.org/10.1038/ng.3771},
  volume       = {49},
  year         = {2017},
}