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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)341-348
Number of pages8
JournalNature genetics
Volume49
Issue number3
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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