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.

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Citation

Published Version (Please cite this version)

10.18632/oncotarget.588

Publication Info

Jiao, Yuchen, Patrick J Killela, Zachary J Reitman, Ahmed B Rasheed, Christopher M Heaphy, Roeland F de Wilde, Fausto J Rodriguez, Sergio Rosemberg, et al. (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.

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Scholars@Duke

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

Pirozzi

Christopher Pirozzi

Assistant Professor in 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 patients with astrocytomas or oligodendrogliomas on a genetic level which can complement the difficult work of neuropathologists and better direct patient therapeutics. Christopher utilized these mutations as a foundation for animal modeling, leading to genetically faithful and biologically relevant systems that are applied to both basic research to understand the pathogenic nature of these mutations, as well as pre-clinical and translational research to understand how best to treat these tumors. Christopher’s work in animal modeling and understanding mutant IDH1-mediated gliomagenesis was recognized in several forms including first place winner of the Duke University School of Medicine’s Clinical Research Day poster session, being an invited speaker at the annual Department of Pathology’s Retreat, and as the recipient of the Robert and Barbara Bell Basic Science Cancer Research Award recognized at the Fifth Annual DCI Scientific Retreat in 2017.

Dr. Pirozzi is currently working on utilizing those mutations identified in the human genetic screens for immunotherapeutic purposes. He has generated a series of orthotopic intracranial injection-based immune-competent animal models for which he is actively investigating the impact the mutations have on the tumor-immune microenvironment and whether the tumor-immune microenvironment can be manipulated to promote an anti-tumor response. Specifically, his most recently funded Department of Defense Idea Award with Special Focus entails understanding the impact mutant IDH1 is having on the Th17 T cell lineage and whether this can be exploited for therapeutic purposes. 

Christopher contributed to the successful funding of several grants including a Duke Cancer Institute Cancer Research Pilot Grant as well as an R33, focusing on the identification and cloning of mutation-specific T cell receptors that could be used for adoptive transfer. Understanding the tumor-immune microenvironment and whether it can be manipulated to improve therapeutics or promote an anti-tumor immune response, and the identification of tumor-specific therapies that will avoid collateral damage to the sensitive brain are active lines of investigation.

López

Giselle Yvette López

Associate 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. Clinically, I specialize in neuropathology. While I have active projects and collaborations on many kinds of brain tumors, my lab's primary focus is oligodendroglioma, a kind of infiltrative brain tumor that impacts adults. Our goal is to identify new ways to treat these tumors and improve the lives of patients with oligodendrogliomas and other kinds of brain tumors. By blending together computational approaches with wet lab approaches, we use the strengths inherent in different research modalities to excel in identifying unexplored pathways and thinking outside the box to identify new ways to target this brain tumor.  We do this through research in an inclusive, multidisciplinary lab environment that strives for excellence in research while creating well-rounded, thriving scientists ready for the next step in their careers.

Research Opportunities
We currently have opportunities in the laboratory for one-year projects (ideal for post-bac fellows or third year med student research experiences), as well as more extensive projects (graduate student-level). These projects are centered on identifying and testing novel therapeutic approaches for oligodendroglioma using in vitro and in vivo model systems. Please reach out if you are interested and would like to hear more about my mentoring philosophy, lab culture, and opportunities to be at the cutting edge of science.

He

Yiping He

Associate Professor in Pathology
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 athymic nude rats, and patients tumor specimens, are defining:

1) the chemotherapeutic profile of medulloblastoma, adult and childhood glioma and ependymoma
2) mechanisms of resistance to classical bifunctional alkylators, nitrosoureas and methylators operational in malignant glioma and medulloblastoma, particularly DNA adduct and crosslink repair, O6-alkylguanine-DNA alkyltransferase elevation and DNA mismatch repair deficiency.
3) modulations designed to over come or circumvent specific mechanisms of resistance
4) the activity of signal pathway inhibitors of EGFR, m-tor and other targets
5) the therapeutic advantages of intrathecal and intratumoral drug delivery in the treatment of neoplastic meningitis and intracranial malignancies, respectively.

The results of the therapeutic studies to date have demonstrated the marked activity of alkylating agents, particularly melphalan and cyclophosphamide and the role of glutathione, AGT glutathione-S-transferase, abnormal drug transport and alterations in formation and repair of DNA-DNA crosslinks in modulating cytotoxicity of these agents. Modulations shown to be effective in enhancing alkylator activity/reversing alkylator resistance include BSO-mediated glutathione depletion, inhibition of DNA-DNA crosslink repair and inhibition of 06-alkylguanine-DNA alkyltransferase by 06-benzylguanine. Recent studies have demonstrated profound activity of temozolomide, CPT-11 topotecan, irofulven, and karenitecin as well as the combination of CPT-11 or topotecan plus BCNU or temozolomide. Successful treatment of neoplastic meningitis in nude rats with intrathecal 4-hydroperoxycyclophosphamide, melphalan, temozolomide and busulfan, and intracranial glioma in nude rats with intratumoral temozolomide has also been demonstrated. More recent studies have revealed cyclophosphamide resistance secondary to DNA interstrand crosslink repair. Additional studies have shown that cyclophosphamide crosslinks are formed at the 1,3 N7 position, serving as the basis for construction of a defined crosslink in a plasmid vector to assay for crosslink repair and allowing demonstration of the lack of a role of nucleotide excision repair. Mismatch repair deficiency has been shown as a mechanism mediating acquired methylator (procarbazine and temozolomide) resistance in an adult glioblastoma xenograft.

Clinical Studies: Clinical investigations are designed to translate laboratory programs into successful treatment for adults and children with malignant brain tumors, particularly medulloblastoma. Clinical trials for adults include phase II trials of temozolomide, ZD1839 (Iressa), karenitecin, and temozolomide plus O6-BG as well as phase I trials of topotecan plus BCNU, CPT-11 plus temozolomide, and PTK787 ± temozolomide or CCNU. Studies are in progress in children evaluating the activity CPT-11 plus temozolomide, intrathecal busulfan and cyclophosphamide/melphalan or cyclophosphamide/busulfan plus autologous bone marrow support . Extension of these studies to a larger cohort of patients is being performed nationally under the auspices of the Pediatric Brain Tumor Consortium (Henry S. Friedman -- Head of New Agents Committee).

Future studies will address the role of agents designed to decrease repair of interstrand crosslinks when given in combination with alkylating agents, as well as newer signal pathway inhibitors such as RAD001, PKI166, and DB-67.

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 collaboration with the Division of Neurology and the Department of Pathology, clinical and laboratory trials have been initiated to identify better treatment for this condition. At present, trials of monoclonal antibodies and novel chemotherapeutic agents are being carried out.

Although physicians have been interested in seizures since the time of Hippocrates, the origin of seizures remains obscure. At Duke University we have treated approximately thirty seizure patients a year by removing abnormal portions of brain. Tissue from these resections is being analyzed for genetics and receptor abnormalities. Positron emission tomography and magnetic resonance imaging are being used to ferret out the origin of the patient's seizures.

Approximately 28,000 patients each year suffer a ruptured intracranial aneurysm. Approximately ten percent of these patients have a genetic predisposition to forming intracranial aneurysms. In conjunction with the Division of Neurology, we are screening candidate genes searching for the cause of intracranial aneurysms.

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 understand the processes involved in the etiology, pathogenesis, and treatment of brain tumors.  Using the resources of the Preston Robert Brain Tumor Biorepository at Duke, our team, consisting of Henry Friedman, Allan Friedman, and Hai Yan and lead by Darell Bigner, have helped to identify mutations in Isocitrate Dehydrogenase (IDH1 and IDH2) as a marker of good prognosis in gliomas of adults.  This test is now offered at Duke as a clinical test.  Working with the Molecular Pathology Laboratory at Duke, we have also brought testing for TERT promoter region mutations as another major test for classifying gliomas in adults.  Our collaboration with the Toronto Sick Kids Hospital has resulted in prognostic testing for childhood medulloblastomas, primitive neuroectodermal tumors, and ependymomas at Duke.


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