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

Abstract

// Yuchen Jiao 1,* , Patrick J. Killela 2,* , Zachary J. Reitman 2,* , B. Ahmed Rasheed 2 , Christopher M. Heaphy 1 , Roeland F. de Wilde 1 , Fausto J. Rodriguez 1 , Sergio Rosemberg 3 , Sueli Mieko Oba-Shinjo 3 , Suely Kazue Nagahashi Marie 3 , Chetan Bettegowda 1 , Nishant Agrawal 1 , Eric Lipp 2 , Christopher J. Pirozzi 2 , Giselle Y. Lopez 2 , Yiping He 2 , Henry S. Friedman 2 , Allan H. Friedman 2 , Gregory J. Riggins 1 , Matthias Holdhoff 1,4 , Peter Burger 1 , Roger E. McLendon 2 , Darell D. Bigner 2 , Bert Vogelstein 1 , Alan K. Meeker 1 , Kenneth W. Kinzler 1 , Nickolas Papadopoulos 1 , Luis A. Diaz Jr 1,4 , Hai Yan 2 1 Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, The Johns Hopkins Kimmel Cancer Center, the Department of Oncology, the Department of Pathology, the Department of Neurosurgery, the Johns Hopkins Medical Institutions, Baltimore, Maryland, USA 2 The Preston Robert Tisch Brain Tumor Center at Duke, The Pediatric Brain Tumor Foundation Institute, the Department of Pathology, the Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA 3 The Department of Pathology, the Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil 4 The Swim Across America Laboratory at Johns Hopkins, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA * Denotes equal contribution Correspondence: Hai Yan, email: // Luis Diaz, email: // Keywords : ALT, IDH1, IDH2, Mixed Gliomas Received : July 31, 2012, Accepted : August 2, 2012, Published : August 3, 2012 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 mutationsin 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 (<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.