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染色体外致癌基因扩增驱动肿瘤进化和基因异质性。

Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity.

作者信息

Turner Kristen M, Deshpande Viraj, Beyter Doruk, Koga Tomoyuki, Rusert Jessica, Lee Catherine, Li Bin, Arden Karen, Ren Bing, Nathanson David A, Kornblum Harley I, Taylor Michael D, Kaushal Sharmeela, Cavenee Webster K, Wechsler-Reya Robert, Furnari Frank B, Vandenberg Scott R, Rao P Nagesh, Wahl Geoffrey M, Bafna Vineet, Mischel Paul S

机构信息

Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.

Department of Computer Science and Engineering, University of California at San Diego, La Jolla, California 92093, USA.

出版信息

Nature. 2017 Mar 2;543(7643):122-125. doi: 10.1038/nature21356. Epub 2017 Feb 8.

Abstract

Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

摘要

人类细胞有23对染色体。然而,在癌症中,基因可在染色体或环状染色体外DNA(ecDNA)中扩增,尽管ecDNA的频率和功能重要性尚不清楚。我们对17种不同癌症类型进行了全基因组测序、结构建模和细胞遗传学分析,包括对2572个分裂细胞中期染色体的结构和功能分析,并开发了一个名为ECdetect的软件包,以进行无偏倚的、综合的ecDNA检测和分析。我们在此表明,在近一半的人类癌症中发现了ecDNA;其频率因肿瘤类型而异,但在正常细胞中几乎从未发现。驱动癌基因最常在ecDNA中扩增,从而提高转录水平。数学建模预测,ecDNA扩增比染色体扩增更有效地增加癌基因拷贝数和肿瘤内异质性。我们通过对癌症样本的定量分析验证了这些预测。此处呈现的结果表明,ecDNA有助于癌症的加速进化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6b7/5334176/22683676b2fd/nihms839083f5.jpg

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