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

作者：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

来源：Nature Genetics, 2017, 49(3): 341-348.

DOI：10.1038/ng.3771

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.

• 出版日期2017-3