RT Journal Article
SR Electronic
T1 Extrachromosal DNA elements can drive disease evolution in glioblastoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 081158
DO 10.1101/081158
A1 Ana C. deCarvalho
A1 Hoon Kim
A1 Laila M. Poisson
A1 Mary E. Winn
A1 Claudius Mueller
A1 David Cherba
A1 Julie Koeman
A1 Sahil Seth
A1 Alexei Protopopov
A1 Michelle Felicella
A1 Siyuan Zheng
A1 Jianhua Zhang
A1 Emanuel F. Petricoin
A1 Lynda Chin
A1 Tom Mikkelsen
A1 Roel G.W. Verhaak
YR 2016
UL http://biorxiv.org/content/early/2016/10/14/081158.abstract
AB To understand how genomic heterogeneity of glioblastoma (GBM) contributes to the poor response to therapy which is characteristic of this disease, we performed DNA and RNA sequencing on primary GBM, neurospheres and orthotopic xenograft models derived from the same parental tumor. We used these data to show that somatic driver alterations were in majority propagated from tumor to model systems. In contrast, we found that amplifications of MET, a proto-oncogene coding for a receptor tyrosine kinase, were detected in three of thirteen primary GBM, largely discarded in neurospheres cultures, but resurfaced in xenografts. We inferred the clonal evolution dynamics of all models using somatic single nucleotide variants (sSNVs) and were unable to find sSNVs replicating the pattern delineated by the MET amplification event despite its strong selective effect. FISH analysis showed that most copies of MET resided on extrachromosomal DNA elements commonly referred to as double minutes. Long range Pacific Biosciences sequencing recovered the MET containing circular double minute structure. The evolutionary propagation patterns suggested that MET double minutes and sSNVs were disjointly inherited. The context-dependent reemergence of MET amplifiations suggests that the microenvironmental milieu was a critical regulator of extrachromosomal MET driven cell proliferation. Our analysis shows that extrachromosomal elements are able to drive tumor evolution.