染色体外DNA
生物
遗传学
神经球
DNA
基因组
癌症研究
基因
细胞分化
成体干细胞
作者
Ana C. deCarvalho,Hoon Kim,Laila Poisson,Mary E. Winn,Claudius Mueller,David Cherba,Julie Koeman,Sahil Seth,Alexei Protopopov,Michelle M. Felicella,Siyuan Zheng,Asha S. Multani,Yongying Jiang,Jianhua Zhang,Do‐Hyun Nam,Emanuel F. Petricoin,Lynda Chin,Tom Mikkelsen,Roel G.W. Verhaak
出处
期刊:Nature Genetics
[Nature Portfolio]
日期:2018-04-20
卷期号:50 (5): 708-717
被引量:279
标识
DOI:10.1038/s41588-018-0105-0
摘要
To understand how genomic heterogeneity of glioblastoma (GBM) contributes to poor therapy response, we performed DNA and RNA sequencing on GBM samples and the neurospheres and orthotopic xenograft models derived from them. We used the resulting dataset to show that somatic driver alterations including single-nucleotide variants, focal DNA alterations and oncogene amplification on extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, ecDNAs and chromosomal alterations demonstrated divergent inheritance patterns and clonal selection dynamics during cell culture and xenografting. We infer that ecDNA was unevenly inherited by offspring cells, a characteristic that affects the oncogenic potential of cells with more or fewer ecDNAs. Longitudinal patient tumor profiling found that oncogenic ecDNAs are frequently retained throughout the course of disease. Our analysis shows that extrachromosomal elements allow rapid increase of genomic heterogeneity during GBM evolution, independently of chromosomal DNA alterations. Analysis of glioblastoma samples and derived neurospheres and xenografts shows that chromosomal and extrachromosomal alterations often display divergent inheritance patterns during cell culture and xenografting.
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