TY - JOUR
T1 - ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma
AU - Koschmann, Carl
AU - Calinescu, Anda Alexandra
AU - Nunez, Felipe J.
AU - Mackay, Alan
AU - Fazal-Salom, Janet
AU - Thomas, Daniel
AU - Mendez, Flor
AU - Kamran, Neha
AU - Dzaman, Marta
AU - Mulpuri, Lakshman
AU - Krasinkiewicz, Johnathon
AU - Doherty, Robert
AU - Lemons, Rosemary
AU - Brosnan-Cashman, Jaqueline A.
AU - Li, Youping
AU - Roh, Soyeon
AU - Zhao, Lili
AU - Appelman, Henry
AU - Ferguson, David
AU - Gorbunova, Vera
AU - Meeker, Alan
AU - Jones, Chris
AU - Lowenstein, Pedro R.
AU - Castro, Maria G.
N1 - Funding Information:
We thank J. Ohlfest (University of Minnesota, deceased) for his support of our implementation of the SB model. C.K. wishes to thank P. Robertson and H. Garton for their academic support. We gratefully acknowledge P. Jenkins and the Department of Neurosurgery at the University of Michigan Medical School for their support of our work. We are also grateful to K. Muraszko for her academic leadership and D. Tomford, S. Napolitan, M. Dahlgren, and C. Shaw for superb administrative support. This study makes use of data generated by the St. Jude Children?s Research Hospital?Washington University Pediatric Cancer Genome Project, the principal investigator C. Hawkins and the Hospital for Sick Children, the McGill University Health Centre and the DKFZ (Deutsches Krebsforschungszentrum)?University of Heidelberg Pediatric Brain Tumour Consortium, and the Institute of Cancer Research (ICR)?Institut Gustav Roussy?Hospital Sant Joan de D?u collaborative group. Funding: This work was supported by NIH/National Institute of Neurological Disorders and Stroke (NINDS) grants 1RO1-NS 054193, 1RO1-NS 061107, and 1RO1-NS082311 to P.R.L.; grants 1UO1-NS052465, 1RO1-NS 057711, and 1RO1-NS074387 to M.G.C., and grant NIH/National Cancer Institute R01CA172380 to A. Meeker. C.K. was supported by the St. Baldrick?s Foundation Fellowship and the Alex?s Lemonade Stand Foundation/Northwestern Mutual Young Investigator Grant. C.J., A. Mackay, and J.F.-S. acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre at The Royal Marsden and the ICR, and the INSTINCT network funded by The Brain Tumour Charity, Great Ormond Street Hospital Children?s Charity, and Children with Cancer UK. Author contributions: C.K. carried out the animal and in vitro studies and drafted the manuscript. A.-A.C., F.J.N., D.T., F.M., N.K., M.D., L.M., J.K., R.L., Y.L., and S.R. participated in the animal and in vitro studies. L.Z. performed statistical analysis. A. Meeker and J.A.B.-C. assisted with the design and interpretation of ALT studies (FISH and c-circle). H.A. provided human PanNET samples. D.F. assisted with the design and interpretation of metaphase preparation/ chromosome counting. A. Mackay, J.F.-S., and C.J. performed analysis of human pediatric glioma data sets. V.G. assisted with the design and interpretation of DDR plasmid assays. M.G.C. and P.R.L. conceived and supervised the study, participated in its design and coordination, and helped to draft and edit the manuscript. All authors read and approved the final manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: We have deposited previously unpublished sequence data for additional pediatric highgrade glioma samples (C.J., EGAS00001001436).
Publisher Copyright:
© 2016 by the American Association for the Advancement of Science; all rights reserved.
PY - 2016/3/2
Y1 - 2016/3/2
N2 - Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.
AB - Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.
UR - http://www.scopus.com/inward/record.url?scp=84959523012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84959523012&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aac8228
DO - 10.1126/scitranslmed.aac8228
M3 - Article
C2 - 26936505
AN - SCOPUS:84959523012
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 328
M1 - 328ra28
ER -