July 19, 2019  |  

Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma.

Authors: deCarvalho, Ana C and Kim, Hoon and Poisson, Laila M and Winn, Mary E and Mueller, Claudius and Cherba, David and Koeman, Julie and Seth, Sahil and Protopopov, Alexei and Felicella, Michelle and Zheng, Siyuan and Multani, Asha and Jiang, Yongying and Zhang, Jianhua and Nam, Do-Hyun and Petricoin, Emanuel F and Chin, Lynda and Mikkelsen, Tom and Verhaak, Roel G W

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.

Journal: Nature genetics
DOI: 10.1038/s41588-018-0105-0
Year: 2018

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