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Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.

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Date
2012-07
Authors
Jiao, Yuchen
Killela, Patrick J
Reitman, Zachary J
Rasheed, Ahmed B
Heaphy, Christopher M
de Wilde, Roeland F
Rodriguez, Fausto J
Rosemberg, Sergio
Oba-Shinjo, Sueli Mieko
Nagahashi Marie, Suely Kazue
Bettegowda, Chetan
Agrawal, Nishant
Lipp, Eric
Pirozzi, Christopher
Lopez, Giselle
He, Yiping
Friedman, Henry
Friedman, Allan H
Riggins, Gregory J
Holdhoff, Matthias
Burger, Peter
McLendon, Roger
Bigner, Darell D
Vogelstein, Bert
Meeker, Alan K
Kinzler, Kenneth W
Papadopoulos, Nickolas
Diaz, Luis A
Yan, Hai
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(29 total)
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Abstract
Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.
Type
Journal article
Subject
Telomere
Humans
Glioma
Brain Neoplasms
DNA Helicases
Isocitrate Dehydrogenase
DNA-Binding Proteins
Nuclear Proteins
Repressor Proteins
Prognosis
Immunohistochemistry
Gene Silencing
Mutation
Adult
Female
Male
Neoplasm Grading
Permalink
https://hdl.handle.net/10161/17849
Published Version (Please cite this version)
10.18632/oncotarget.588
Publication Info
Jiao, Yuchen; Killela, Patrick J; Reitman, Zachary J; Rasheed, Ahmed B; Heaphy, Christopher M; de Wilde, Roeland F; ... Yan, Hai (2012). Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget, 3(7). pp. 709-722. 10.18632/oncotarget.588. Retrieved from https://hdl.handle.net/10161/17849.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Bigner

Darell Doty Bigner

E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine
The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS). There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to
Friedman

Allan Howard Friedman

Guy L. Odom Distinguished Professor of Neurosurgery, in the School of Medicine
At the present time, I am participating in collaborative research in the areas of primary malignant brain tumors, epilepsy and subarachnoid hemorrhage. Primary malignant brain tumors are increasing in frequency. Patients harboring glioblastoma, the most malignant primary brain tumor, have a life expectancy of less than one year. In colloboration with the Division of Neurology and the Department of Pathology, clinical and laboratory trials have been initiated to identify better
Friedman

Henry Seth Friedman

James B. Powell, Jr. Distinguished Professor of Pediatric Oncology, in the School of Medicine
Overview: Our laboratory is pursuing a comprehensive analysis of the biology and therapy of adult and childhood central nervous system malignancies, particularly high-grade medulloblastoma, glioma, and ependymoma. Laboratory Studies: Active programs, using human adult and pediatric CNS tumor continuous cell lines, transplantable xenografts growing subcutaneously and intracranially in athymic nude mice and rats, and as well as in the subarachnoid space of the ath
He

Yiping He

Associate Professor in Pathology
López

Giselle Yvette López

Assistant Professor in Pathology
I am a physician scientist with a clinical focus on neuropathology, and a research interest in brain tumors. Originally from Maryland, I completed my undergraduate training at the University of Maryland, completing degrees in Physiology and Neurobiology as well as Spanish Language and Literature. I subsequently came to Duke for my MD and PhD, and discovered a passion for brain tumor research, and quickly realized that this was my life's calling. After completing a residency and fellowship at the
McLendon

Roger Edwin McLendon

Professor of Pathology
Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum.  My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understan
Pirozzi

Christopher Pirozzi

Medical Instructor in the Department of Pathology
Dr. Pirozzi's work thus far has been dedicated to studying brain tumors, particularly gliomas. During his research career, he has focused on identifying the common mutations present in gliomas and how these different mutations correlate with diagnoses and prognoses. To this end, Christopher was involved in several publications that identified and stratified brain tumor patients based on their mutation spectrum. For example, mutations in ATRX, CIC, FUBP1, and IDH1 can be used to distinguish pa

B. K. Ahmed Rasheed

Assistant Professor in Pathology
Our lab is interested in identifying the specific genetic alterations associated with the genesis and progression of glial malignancies. Studies from our and other laboratories have shown that in adult glioblastomas, approximately 80% of the cases show loss of alleles on chromosome 10, and to a lesser extent on 9p, 17p, 19q and 22q. Amplification of epidermal growth factor receptor gene is detected in about a third of glioblastomas. The high incidence of loss of chromosome 10 alleles sug
Reitman

Zachary James Reitman

Assistant Professor of Radiation Oncology
Dr. Reitman’s clinical interests include radiotherapy for primary and metastatic tumors of the brain and spine.  He is also interested in basic and translational research studies to develop new treatment approaches for pediatric and adult brain tumors.  He uses genomic analysis, radiation biology studies, and genetically engineered animal models of cancer to carry out this research
Yan

Hai Yan

Adjunct Professor of Pathology
Our research activities center on the molecular genetics and biology of cancer with a focus on the identification, characterization, and therapeutic targeting of driver mutations involved in the genesis and progression of brain cancers.  Gliomas are the most common type of primary brain tumor. Through genomic studies, we have identified mutations in IDH1 and IDH2 in 70% of progressive malignant gliomas. These are somatic missense mutations that alter a conserved arginine residue and gain a
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