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

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

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)708-717
Number of pages10
JournalNature Genetics
Volume50
Issue number5
DOIs
StatePublished - May 1 2018

ASJC Scopus subject areas

  • Genetics

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