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

Ana C deCarvalho
Hoon Kim, The Jackson Laboratory
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, The Jackson Laboratory


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 Apr 23 [Epub ahead of print]