Format

Send to

Choose Destination
Nat Genet. 2018 May;50(5):708-717. doi: 10.1038/s41588-018-0105-0. Epub 2018 Apr 23.

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

Author information

1
Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA. adecarv1@hfhs.org.
2
Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
3
Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
4
Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI, USA.
5
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
6
Genomics Core, Van Andel Research Institute, Grand Rapids, MI, USA.
7
Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Pathology, Henry Ford Hospital, Detroit, MI, USA.
9
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10
Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
11
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
12
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
13
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
14
Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA. tmikkel1@hfhs.org.
15
Department of Neurology, Henry Ford Hospital, Detroit, MI, USA. tmikkel1@hfhs.org.
16
Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. roel.verhaak@jax.org.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center