期刊
NATURE GENETICS
卷 52, 期 9, 页码 891-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-0678-2
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资金
- Ludwig Institute for Cancer Research
- Defeat GBM Program of the National Brain Tumor Society
- NVIDIA Foundation, Compute for the Cure
- Ben and Catherine Ivy Foundation
- Ruth L. Kirschstein National Research Service Award
- National Institutes of Health [NS73831, GM114362, R01 CA190121, R01 CA237208, R21 NS114873]
- Cancer Center Support Grant [P30 CA034196, R35CA209919, RM1-HG007735, R35GM133600]
- National Science Foundation [NSF-IIS-1318386, NSF-DBI-1458557]
- Musella Foundation
- B*CURED Foundation
- Brain Tumour Charity
- Department of Defense [W81XWH1910246]
- U.S. Department of Defense (DOD) [W81XWH1910246] Funding Source: U.S. Department of Defense (DOD)
Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution(1-3); however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types. A pan-cancer analysis finds that extrachromosomal DNA is pervasive and associated with oncogene amplification and poor patient outcomes.
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