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

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 gl...

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Published in:Oncotarget 2012-07, Vol.3 (7), p.709-722
Main 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
Format: Article
Language:English
Subjects:
Adult
Brain Neoplasms - classification
Brain Neoplasms - genetics
Brain Neoplasms - pathology
DNA Helicases - genetics
DNA-Binding Proteins - genetics
Female
Gene Silencing
Glioma - classification
Glioma - genetics
Glioma - pathology
Humans
Immunohistochemistry
Isocitrate Dehydrogenase - genetics
Male
Mutation
Neoplasm Grading
Nuclear Proteins - genetics
Prognosis
Repressor Proteins - genetics
Research Papers
Telomere - genetics
X-linked Nuclear Protein
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.588