期刊
NATURE GENETICS
卷 49, 期 3, 页码 341-348出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3771
关键词
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资金
- ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project - European Community's Seventh Framework Programme [242006]
- Triple Negative project
- Wellcome Trust [077012/Z/05/Z]
- HER2+ project
- Institut National du Cancer (INCa) in France [226-2009, 02-2011, 41-2012, 144-2008, 06-2012]
- ERC Advanced grant [322737]
- National Research Foundation of Korea [NRF 2015R1A2A1A10052578]
- grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A111218-SC01]
- EU-FP7-SUPPRESSTEM project
- Wellcome Trust Intermediate Fellowship [WT100183MA]
- Wellcome Beit Fellow
- Cancer Research UK [19013, 23916, 22932, 12077, 23433, 22585, 20952] Funding Source: researchfish
- European Research Council (ERC) [322737] Funding Source: European Research Council (ERC)
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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