期刊
CANCER CELL
卷 34, 期 2, 页码 197-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.06.008
关键词
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资金
- NCI [P30CA034196]
- DoD CDMRP [W81XWH-17-1-0005, W81XWH-17- 1-0006]
- Andrea Branch and David Elliman Cancer Study Fund
- Scott R. MacKenzie Foundation
- NIH grant [R01CA190121]
- CPRIT grant [R140606]
- NWO/ZonMW Vici grant [91814643]
- ERC Synergy [319661]
- Cancer Genomics Netherlands
- Oncode Institute - Dutch Cancer Society
- Gil Ehrich Foundation
- European Research Council (ERC) [319661] Funding Source: European Research Council (ERC)
The tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian, and endometrial carcinomas. Here, we stratify TDP tumors by classifying their tandem duplications (TDs) into three span intervals, with modal values of 11 kb, 231 kb, and 1.7 Mb, respectively. TDPs with similar to 11 kb TDs feature loss of TP53 and BRCA1. TDPs with similar to 231 kb and similar to 1.7 Mb TDs associate with CCNE1 pathway activation and CDK12 disruptions, respectively. We demonstrate that p53 and BRCA1 conjoint abrogation drives TDP induction by generating short-span TDP mammary tumors in genetically modified mice lacking them. Lastly, we show how TDs in TDP tumors disrupt heterogeneous combinations of tumor suppressors and chromatin topologically associating domains while duplicating oncogenes and super-enhancers.
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