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Search Results for all work with filters:

  • Biology, Neuroscience
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Work 1-5 of 5

Sorted by relevance

Article

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

by Marc Remke; Vijay Ramaswamy; John Peacock; David J. H. Shih; Christian Koelsche; Paul A. Northcott; Nadia Hill; Florence M. G. Cavalli; Marcel Kool; Xin Wang; Stephen C. Mack; Mark Barszczyk; A. Sorana Morrissy; Xiaochong Wu; Sameer Agnihotri; Betty Luu ; David T.W. Jones; Livia Garzia; Adrian M. Dubuc; Nataliya Zhukova; Robert Vanner; Johan M. Kros; Pim J. French; Erwin Van Meir; Rajeev Vibhakar; Karel Zitterbart; Jennifer A. Chan; Laszlo Bognar; Almos Klekner; Boleslaw Lach ; Shin Jung; Ali G. Saad; Linda M. Liau; Steffen Albrecht; Massimo Zollo; Michael Cooper; Reid C. Thompson; Oliver O. Delattre; Franck Bourdeaut; Francois F. Doz; Miklos Garami; Peter Hauser; Carlos G. Carlotti; Timothy E. Van Meter; Luca Massimi; Daniel Fults; Scott L. Pomeroy; Toshiro Kumabe ; Young Shin Ra; Jeffrey R. Leonard; Samer K. Elbabaa; Jaume Mora; Joshua B. Rubin; Yoon-Jae Cho; Roger E. McLendon; Darrell D. Bigner; Charles G. Eberhart; Maryam Fouladi; Robert J. Wechsler-Reya; Claudia C. Faria; Sidney E. Croul; Annie Huang ; Eric Bouffet; Cynthia E. Hawkins ; Peter B. Dirks; William A. Weiss ; Ulrich Schuller; Ian F. Pollack; Stefan Rutkowski; David Meyronet; Anne Jouvet; Michelle Fevre-Montange; Nada Jabado; Marta Perek-Polnik; Wieslawa A. Grajkowska; Seung-Ki Kim; James T. Rutka ; David Malkin; Uri Tabori; Stefan M. Pfister; Andrey Korshunov; Andreas von Deimling

2013

Subjects
  • Biology, Neuroscience
  • Health Sciences, Pathology
  • File Download
  • View Abstract

Abstract:Close

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in < 5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Article

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

by Peng Yin; Xiangyu Guo; Weili Yang; Sen Yan; Su Yang; Ting Zhao; Qiang Sun; Yunbo Liu; Shihua Li; Xiao-Jiang Li

2019

Subjects
  • Biology, Neuroscience
  • Biology, Genetics
  • File Download
  • View Abstract

Abstract:Close

The cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. The primate-specific caspase-4, but not mouse homologue caspase-11, could remove the NLS-containing N-terminal domain and generate fragmented TDP-43 that accumulates in the cytoplasm. Moreover, increased expression of caspase-4 in the monkey brain promotes the cytoplasmic accumulation of endogenous TDP-43, and suppressing caspase-4 reduces the cytoplasmic distribution of endogenous TDP-43 in cultured human neural cells. Our findings suggest that primate-specific caspase-4-mediated cleavage of TDP-43 accounts for its cytoplasmic mislocalization in the primate brains and may serve as a potential therapeutic target.

Article

PDGFRA Amplification is Common in Pediatric and Adult High-Grade Astrocytomas and Identifies a Poor Prognostic Group in IDH1 Mutant Glioblastoma

by Joanna J. Phillips; Derick Aranda; David W. Ellison; Alexander R. Judkins; Sidney E. Croul; Daniel J Brat; Keith L. Ligon; Craig Horbinski; Sriram Venneti; Gelareh Zadeh; Mariarita Santi; Shengmei Zhou; Christina L. Appin; Stefano Sioletic; Lisa M. Sullivan; Maria Martinez-Lage; Aaron E. Robinson; William H. Yong; Timothy Cloughesy; Albert Lai; Heidi S. Phillips; Roxanne Marshall

2013

Subjects
  • Health Sciences, Pathology
  • Biology, Neuroscience
  • File Download
  • View Abstract

Abstract:Close

High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1) R132H mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.

Article

Glioblastoma with Oligodendroglioma Component (GBM-O): Molecular Genetic and Clinical Characteristics

by Christina L. Appin; Jingjing Gao; Candace Chisolm; Mike Torian; Dianne Alexis; Cristina Vincentelli; Matthew Schniederjan; Constantinos Hadjipanayis; Jeffrey Olson; Stephen Hunter; Chunhai Hao; Daniel Brat

2013

Subjects
  • Biology, Neuroscience
  • Health Sciences, Oncology
  • Health Sciences, Pathology
  • File Download
  • View Abstract

Abstract:Close

Glioblastoma (GBM) is an aggressive primary brain tumor with an average survival of approximately 1 year. A recently recognized subtype, glioblastoma with oligodendroglioma component (GBM-O), was designated by the World Health Organization (WHO) in 2007. We investigated GBM-Os for their clinical and molecular characteristics as compared to other forms of GBM. Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation-specific polymerase chain reaction (PCR). GBM-Os accounted for 11.9% of all GBMs. GBM-Os arose in younger patients compared to other forms of GBMs (50.7 years vs. 58.7 years, respectively), were more frequently secondary neoplasms, had a higher frequency of IDH1 mutations and had a lower frequency of PTEN deletions. Survival was longer in patients with GBM-Os compared to those with other GBMs, with median survivals of 16.2 and 8.1 months, respectively. Most of the survival advantage for GBM-O appeared to be associated with a younger age at presentation. Among patients with GBM-O, younger age at presentation and 1p deletion were most significant in conferring prolonged survival. Thus, GBM-O represents a subset of GBMs with distinctive morphologic, clinical and molecular characteristics.

Article

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

by Amanda M. Saratsis; Madhuri Kambhampati; Kendall Snyder; Sridevi Yadavilli; Joe Devaney; Brennan Harmon; Jordan Hall; Eric H. Raabe; Ping An; Melanie Weingart; Brian R. Rood; Suresh Magge; Tobey MacDonald; Roger J. Packer; Javad Nazarian

2014

Subjects
  • Biology, Neuroscience
  • Health Sciences, Oncology
  • Health Sciences, Medicine and Surgery
  • File Download
  • View Abstract

Abstract:Close

Diffuse intrinsic pontine glioma (DIPG) is a highly morbid form of pediatric brainstem glioma. Here, we present the first comprehensive protein, mRNA, and methylation profiles of fresh-frozen DIPG specimens (n = 14), normal brain tissue (n = 10), and other pediatric brain tumors (n = 17). Protein profiling identified 2,305 unique proteins indicating distinct DIPG protein expression patterns compared to other pediatric brain tumors. Western blot and immunohistochemistry validated upregulation of Clusterin (CLU), Elongation Factor 2 (EF2), and Talin-1 (TLN1) in DIPGs studied. Comparisons to mRNA expression profiles generated from tumor and adjacent normal brain tissue indicated two DIPG subgroups, characterized by upregulation of Myc (N-Myc) or Hedgehog (Hh) signaling. We validated upregulation of PTCH, a membrane receptor in the Hh signaling pathway, in a subgroup of DIPG specimens. DNA methylation analysis indicated global hypomethylation of DIPG compared to adjacent normal tissue specimens, with differential methylation of 24 genes involved in Hh and Myc pathways, correlating with protein and mRNA expression patterns. Sequencing analysis showed c.83A>T mutations in the H3F3A or HIST1H3B gene in 77 % of our DIPG cohort. Supervised analysis revealed a unique methylation pattern in mutated specimens compared to the wild-type DIPG samples. This study presents the first comprehensive multidimensional protein, mRNA, and methylation profiling of pediatric brain tumor specimens, detecting the presence of two subgroups within our DIPG cohort. This multidimensional analysis of DIPG provides increased analytical power to more fully explore molecular signatures of DIPGs, with implications for evaluating potential molecular subtypes and biomarker discovery for assessing response to therapy.
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