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Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers.
Nature Genetics ( IF 30.8 ) Pub Date : 2020-08-17 , DOI: 10.1038/s41588-020-0678-2
Hoon Kim 1 , Nam-Phuong Nguyen 2, 3 , Kristen Turner 3, 4 , Sihan Wu 4 , Amit D Gujar 1 , Jens Luebeck 2, 5 , Jihe Liu 1 , Viraj Deshpande 2, 6 , Utkrisht Rajkumar 2 , Sandeep Namburi 1 , Samirkumar B Amin 1 , Eunhee Yi 1 , Francesca Menghi 1 , Johannes H Schulte 7, 8 , Anton G Henssen 7, 8, 9 , Howard Y Chang 10, 11 , Christine R Beck 1, 12 , Paul S Mischel 4, 13, 14 , Vineet Bafna 2 , Roel G W Verhaak 1
Affiliation  

Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1,2,3; 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.



中文翻译:

染色体外 DNA 与癌基因扩增和多种癌症的不良结果有关。

染色体外 DNA (ecDNA) 扩增促进肿瘤内遗传异质性和加速肿瘤进化1,2,3; 然而,其频率和临床影响尚不清楚。通过对来自 3,212 名癌症患者的全基因组测序数据进行计算分析,我们发现 ecDNA 扩增经常发生在大多数癌症类型中,但不会发生在血液或正常组织中。癌基因在扩增的 ecDNA 上高度富集,最常见的复发癌基因扩增出现在 ecDNA 上。与拷贝数匹配的线性 DNA 相比,EcDNA 扩增导致更高水平的癌基因转录,再加上增强的染色质可及性,并且更频繁地导致转录融合。携带 ecDNA 的癌症患者的生存期显着缩短,即使在控制组织类型的情况下,也比癌症不是由基于 ecDNA 的癌基因扩增驱动的患者。

更新日期:2020-08-17
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