Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.
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 articleSubject
TelomereHumans
Glioma
Brain Neoplasms
DNA Helicases
Isocitrate Dehydrogenase
DNA-Binding Proteins
Nuclear Proteins
Repressor Proteins
Prognosis
Immunohistochemistry
Gene Silencing
Mutation
Adult
Female
Male
Neoplasm Grading
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https://hdl.handle.net/10161/17849Published Version (Please cite this version)
10.18632/oncotarget.588Publication Info
(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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Show full item recordScholars@Duke
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
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
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
Yiping He
Associate Professor in Pathology
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
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
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
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
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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