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

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., Borresen-Dale, Anne-Lise, Richardson, Andrea L., Kong, Gu, Viari, Alain, Easton, Douglas, Evan, Gerard, Campbell, Peter J., Stratton, Michael R. and Nik-Zainal, Serena (2017) A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nature Genetics, 49 3: 341-348. doi:10.1038/ng.3771


Author 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.
Borresen-Dale, Anne-Lise
Richardson, Andrea L.
Kong, Gu
Viari, Alain
Easton, Douglas
Evan, Gerard
Campbell, Peter J.
Stratton, Michael R.
Nik-Zainal, Serena
Title A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
1061-4036
Publication date 2017-03-01
Sub-type Article (original research)
DOI 10.1038/ng.3771
Open Access Status Not yet assessed
Volume 49
Issue 3
Start page 341
End page 348
Total pages 8
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Collection year 2018
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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