Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.
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Frequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.
Published Version (Please cite this version)
Killela, Patrick J, Christopher J Pirozzi, Patrick Healy, Zachary J Reitman, Eric Lipp, B Ahmed Rasheed, Rui Yang, Bill H Diplas, et al. (2014). Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas. Oncotarget, 5(6). pp. 1515–1525. 10.18632/oncotarget.1765 Retrieved from https://hdl.handle.net/10161/16105.
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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.
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
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 suggests the presence of a tumor suppressor gene on this chromosome important in glial tumorigenesis. In an attempt to identify the putative tumor suppressor gene on chromosome 10, we have carried out a detailed deletion mapping of a series of gliomas using RFLP and microsatellite markers. The allelic loss pattern is indicative of a smallest common deletion region on chromosome 10, located between loci D10S587 and D10S216. We are isolating transcribed sequences from this region of chromosome 10 and screening them for presence of somatic mutations in the brain tumors.
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.
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.
Brain Tumors, Preclinical Testing, Translational Research
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.
Current research interests have application to the design and analysis of cancer clinical trials. Specifically, interests include the use of time-dependent covariables within survival models, the design of phase II cancer clinical trials which minimize some of the logistical problems associated with their conduct, and the analysis of longitudinal studies with informative censoring (in particular, quality of life studies of patients with advanced cancer).
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