@article{c428bededfd14b25a3575a7f7267713b,
title = "Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma",
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.",
author = "Decarvalho, {Ana C.} and Hoon Kim and Poisson, {Laila M.} and Winn, {Mary E.} and Claudius Mueller and David Cherba and Julie Koeman and Sahil Seth and Alexei Protopopov and Michelle Felicella and Siyuan Zheng and Asha Multani and Yongying Jiang and Jianhua Zhang and Nam, {Do Hyun} and Petricoin, {Emanuel F.} and Lynda Chin and Tom Mikkelsen and Verhaak, {Roel G.W.}",
note = "Funding Information: The authors would like to thank our colleagues at Henry Ford Hospital: N. Lehman and C. Hao for contributions to pathology reviews; L. Scarpace for clinical information; S. Irtenkauf, L.Hasselbach, K. Nelson, K. Bergman and S. Sobiechowski for cell culture and animal work; and A.Transou, Y. Meng and E. Carlton for histology. We are indebted to M. Wimsatt (JAX) for the creative design in Fig. 6. We thank G. Geneau, S. Roland and PacBio platform personnel of the G{\'e}nome Qu{\'e}bec/Genome Canada–funded Innovation Centre for providing Pacific Biosciences sequencing. AmpliconArchitect analysis of TCGA was made possible through the Cancer Genomics Cloud of the Institute for Systems Biology (ISB-CGC). This work was supported by the LIGHT Research Program at the Hermelin Brain Tumor Center (A.C.d., T.M.); grants from the US National Institutes of Health R01 CA190121 (R.G.W.V.); Cancer Center Support Grant P30CA034196; the Cancer Prevention and Research Institute of Texas (CPRIT) R140606 (R.G.W.V.); and the National Brain Tumor Society (R.G.W.V.). This work was also supported by grant HI14C3418 of the Korea Health Technology R&D project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (D.N.). We are hugely indebted to the patients who provided biospecimens for the purpose of this study. Funding Information: This work was supported by the LIGHT Research Program at the Hermelin Brain Tumor Center (A.C.d., T.M.); grants from the US National Institutes of Health R01 CA190121 (R.G.W.V.); Cancer Center Support Grant P30CA034196; the Cancer Prevention and Research Institute of Texas (CPRIT) R140606 (R.G.W.V.); and the National Brain Tumor Society (R.G.W.V.). This work was also supported by grant HI14C3418 of the Korea Health Technology R&D project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (D.N.). We are hugely indebted to the patients who provided biospecimens for the purpose of this study. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = may,
day = "1",
doi = "10.1038/s41588-018-0105-0",
language = "English (US)",
volume = "50",
pages = "708--717",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "5",
}