Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.
Courtney A. Lovejoy,Wendi Li,Steven Reisenweber,Supawat Thongthip,Joanne Bruno,Titia de Lange,Saurav De,John H.J. Petrini,Patricia Sung,Maria Jasin,Joseph Rosenbluh,Yaara Zwang,Yaara Zwang,Barbara A. Weir,Charlie Hatton,Elena Ivanova,Laura E. MacConaill,Megan Hanna,William C. Hahn,William C. Hahn,Neal F. Lue,Roger R. Reddel,Roger R. Reddel,Yuchen Jiao,Kenneth W. Kinzler,Bert Vogelstein,Nickolas Papadopoulos,Alan K. Meeker +27 more
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TLDR
It is shown that loss of ATRX protein and mutations in the ATRRX gene are hallmarks of ALT–immortalized cell lines, and these attributes will facilitate the diagnosis and treatment ofALT positive human cancers.Abstract:
The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT–immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.read more
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The Somatic Genomic Landscape of Glioblastoma
Cameron Brennan,Roel G.W. Verhaak,Aaron McKenna,Benito Campos,Houtan Noushmehr,Sofie R. Salama,Siyuan Zheng,Debyani Chakravarty,J. Zachary Sanborn,Samuel H. Berman,Rameen Beroukhim,Brady Bernard,Chang-Jiun Wu,Giannicola Genovese,Ilya Shmulevich,Jill S. Barnholtz-Sloan,Lihua Zou,Rahulsimham Vegesna,Sachet A. Shukla,Giovanni Ciriello,W. K. Yung,Wei Zhang,Carrie Sougnez,Tom Mikkelsen,Kenneth Aldape,Darell D. Bigner,Erwin G. Van Meir,Michael D. Prados,Andrew E. Sloan,Keith L. Black,Jennifer M. Eschbacher,Gaetano Finocchiaro,William A. Friedman,David W. Andrews,Abhijit Guha,Mary Iacocca,Brian P. O'Neill,Greg Foltz,Jerome Myers,Daniel J. Weisenberger,Robert Penny,Raju Kucherlapati,Charles M. Perou,D. Neil Hayes,Richard A. Gibbs,Marco A. Marra,Gordon B. Mills,Eric S. Lander,Paul T. Spellman,Richard K. Wilson,Chris Sander,John N. Weinstein,Matthew Meyerson,Stacey Gabriel,Peter W. Laird,David Haussler,Gad Getz,Lynda Chin +57 more
TL;DR: Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM.
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TL;DR: In this article, the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs) was described, including several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA.
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Epidemiologic and Molecular Prognostic Review of Glioblastoma
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TL;DR: The current epidemiology of GBM is reported with new data from the Central Brain Tumor Registry of the United States 2006 to 2010 as well as demonstrate and discuss trends in incidence and survival.
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Whole-genome landscape of pancreatic neuroendocrine tumours
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TL;DR: In this paper, the authors performed whole-genome sequencing of 102 primary pancreatic neuroendocrine tumours and defined the genomic events that characterize their pathogenesis, including a deficiency in G:C,>T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase.
Journal ArticleDOI
Advances in Risk Classification and Treatment Strategies for Neuroblastoma
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TL;DR: Heterogeneous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system and led to advances in understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome.
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