Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma.
Document Type
Article
Publication Date
5-2018
JAX Source
Nat Genet 2018 May; 50(5):708-717.
Volume
50
Issue
5
First Page
708
Last Page
717
ISSN
1546-1718
PMID
29686388
DOI
https://doi.org/10.1038/s41588-018-0105-0
Grant
CA190171, CA034196, R140606, National Brain Tumor Society
Abstract
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. Nat Genet 2018 May; 50(5):708-717.
Recommended Citation
deCarvalho A,
Kim H,
Poisson L,
Winn M,
Mueller C,
Cherba D,
Koeman J,
Seth S,
Protopopov A,
Felicella M,
Zheng S,
Multani A,
Jiang Y,
Zhang J,
Nam D,
Petricoin E,
Chin L,
Mikkelsen T,
Verhaak R.
Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat Genet 2018 May; 50(5):708-717.