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Molecular Subtypes of Anaplastic Oligodendroglioma: Implications for Patient Management at Diagnosis1

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Molecular Subtypes of Anaplastic Oligodendroglioma: Implications for Patient Management at Diagnosis1 Vol. 7, 839–845, April 2001 Clinical Cancer Research 839 Molecular Subtypes of Anaplastic Oligodendroglioma: Implications for Patient Management at Diagnosis1 Yasushi Ino, Rebecca A. Betensky, without TP53 mutations, which are poorly responsive, ag- Magdalena C. Zlatescu, Hikaru Sasaki, gressive tumors that are clinically and genotypically similar David R. Macdonald, to glioblastomas. Conclusions: These data raise the possibility, for the Anat O. Stemmer-Rachamimov, first time, that therapeutic decisions at the time of diagnosis 2 David A. Ramsay, J. Gregory Cairncross, and might be tailored to particular genetic subtypes of anaplastic David N. Louis oligodendroglioma. Molecular Neuro-Oncology Laboratory, Department of Pathology and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School [Y. I., H. S., A. O. S-R., D. N. L.] and Department of INTRODUCTION Biostatistics, Harvard School of Public Health, Boston, Massachusetts Malignant gliomas are the most common type of primary 02114 [R. A. B.], and Departments of Clinical Neurological Sciences, ϳ Oncology, and Pathology, University of Western Ontario and London brain tumor, with 12,000 new cases diagnosed each year in the Regional Cancer Centre, London, Ontario N6A 4L6, Canada United States (1). For nearly a century, malignant gliomas have [M. C. Z., D. R. M., D. A. R., J. G. C.] been classified on the basis of their histological appearance as astrocytomas (including glioblastomas), oligodendrogliomas, ependymomas, or mixed gliomas. For each type, surgical resec- ABSTRACT tion and radiation therapy have been the mainstays of treatment. Purpose: In a prior study of anaplastic oligodendrogli- Cytotoxic drugs have had a relatively minor therapeutic role omas treated with chemotherapy at diagnosis or at recur- because responses to chemotherapy generally have been infre- rence after radiotherapy, allelic loss of chromosome 1p cor- quent, brief, and unpredictable. The only notable exception has related with better chemotherapeutic response and overall been tumors with oligodendroglial histology, which have a survival. However, in this group of patients in whom ther- greater likelihood of radiographic response to chemotherapy. apeutic management was not uniform, loss of 1p did not Unfortunately, the microscopic distinction between high-grade identify all chemosensitive tumors, nor did all patients oligodendrogliomas, which often are chemosensitive, and glio- whose tumors harbor a 1p loss have long survival. blastomas, which are notoriously recalcitrant to the chemother- Experimental Design: To clarify the clinical relevance of apies used at present, is problematic because these two types of molecular genetic testing at the time of diagnosis for patients malignant glioma may share histological features such as small with anaplastic oligodendrogliomas, we studied a larger, cells, vascular proliferation, and necrosis. Such problems raise more homogeneous group of 50 patients with histologically the question of whether histological diagnosis can be refined in defined anaplastic oligodendrogliomas treated with a che- a clinically useful way. Clearly, more precise identification of motherapeutic regimen as the principal initial therapy. chemosensitive tumors and potential long-term survivors at di- Results: We demonstrate that these tumors can be di- agnosis would afford greater flexibility in initial treatment de- vided genetically into four therapeutically and prognosti- cisions for such patients, and improved identification of resistant cally relevant subgroups. Patients whose tumors have com- tumors might justify prescribing novel treatments at diagnosis bined but isolated losses of 1p and 19q have marked and for patients with a poor prognosis (2). With a rational basis for durable responses to chemotherapy associated with long delivering or withholding chemotherapy, effective treatments survival, with or without postoperative radiation therapy. will be appropriately prescribed, and ineffective, toxic, and Other tumors with chromosome 1p alterations also respond costly treatments specifically avoided. to chemotherapy, but with shorter duration of response and Allelic loss of chromosomal arm 1p is emerging as a patient survival. Tumors lacking 1p loss can also be divided marker of chemotherapeutic response (3) and long survival (3, into two subgroups: those with TP53 mutations, which may 4) in patients with histologically defined anaplastic oligoden- also respond to chemotherapy but recur quickly, and those drogliomas. Furthermore, 1p loss may also identify other treat- ment-sensitive malignant gliomas, including rare glioblastomas (5). However, 1p loss does not identify all chemosensitive anaplastic oligodendrogliomas, nor do all patients whose tumors Received 11/16/00; revised 1/8/01; accepted 1/11/01. harbor 1p loss have long survival, although those with chromo- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked some 1p and 19q loss may have particularly favorable outcomes advertisement in accordance with 18 U.S.C. Section 1734 solely to (4). In addition, prior studies included patients treated with a indicate this fact. variety of chemotherapeutic and radiotherapeutic regimens (3, 1 Supported by NIH Grants CA57683 and MRC-MOP-37849. 4). For example, in our previous study, some patients were 2 To whom requests for reprints should be addressed, at London Re- gional Cancer Centre, 790 Commissioners Road, London, Ontario, N6A treated with chemotherapy at diagnosis, whereas others were 4L6 Canada. Phone: (519) 685-8615; Fax: (519) 685-8611; E-mail: treated with radiation therapy at diagnosis and only received [email protected]. chemotherapy at recurrence (3). The practical utility of assess- Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2001 American Association for Cancer Research. 840 Molecular Subtypes of Anaplastic Oligodendroglioma Table 1 Clinical and genetic features oligodendrogliomas, WHO grade III (Fig. 1; Ref. 6). Cases with Number of patients 50 definite astrocytic tumor components were considered oligo- Mean age at diagnosis (range), years 45.3 (17.4–82.1) astrocytomas and excluded. Thirty-four tumors showed radio- M/F 26/24 graphic contrast enhancement, with 9 displaying ring enhance- KPS (median) 80 ment. These investigations have been approved by the Enhancement at diagnosis 34/50 (68%) Massachusetts General Hospital Subcommittee on Human Stud- Ring enhancement at diagnosis 9/50 (18%) 1p LOHa 29/50 (58%) ies and the Review Board for Health Science Research Involv- 19q LOH 33/50 (66%) ing Human Subjects at the University of Western Ontario. None 10q LOH 12/47 (26%) of the patients in this analysis are included in ongoing chemo- PTEN alteration 6/49 (12%) therapy trials for oligodendroglioma. CDKN2A deletion 7/50 (14%) EGFR amplification 7/50 (14%) Molecular Genetic Analysis. Tumor DNA was ex- TP53 mutation 9/50 (18%) tracted from microdissected formalin-fixed, paraffin-embedded a LOH, loss of heterozygosity. sections; constitutional DNA was extracted from blood lympho- cytes or from formalin-fixed, paraffin-embedded sections of adjacent, uninvolved brain or other tissues (7). Allelic chromo- somal loss was assessed by loss of heterozygosity assays in ing chromosome 1p status in anaplastic oligodendrogliomas at constitutional DNA/tumor DNA pairs using microsatellite the time of initial diagnosis, therefore, required clarification. To markers on 1p36.3 (D1S2734, D1S199, and D1S508), 19q13.3 explore further the potential of molecular genetic analysis to (D19S219, D19S112, D19S412, and D19S596), 10q23-24 enhance diagnosis and guide treatment for patients with malig- (D10S185 and D10S2491, near PTEN), and 10q25-26 nant gliomas, we undertook a detailed clinical-molecular genetic (D10S587; Refs. 3, 7). Exons 5–8 of the TP53 gene were correlative study of a larger and more homogeneous set of screened for mutation by single-strand conformation polymor- patients with histologically defined anaplastic oligodendroglio- phism analysis and direct sequencing (8). Exons 1–9 of the mas, all of whom had been treated with a chemotherapeutic PTEN gene were screened for mutations in tumors with 10q regimen as the principal initial therapy. We hypothesized that loss, using similar single-strand conformation polymorphism molecular subtyping could be carried beyond chromosome 1p analysis and sequencing approaches (9). Homozygous deletion analysis and that there were multiple distinct biological types of of the CDKN2A gene and PTEN gene was evaluated by com- anaplastic oligodendroglioma. parative multiplex PCR (10, 11) and EGFR gene amplification by differential PCR (12). MATERIALS AND METHODS Statistical Analysis. The primary goal of the analysis Clinical Parameters. The study included 50 patients was to test the a priori hypothesis that a particular grouping of treated at the London Regional Cancer Center with histologi- the patients according to molecular genetic events is associated cally confirmed anaplastic oligodendrogliomas in whom chem- with chemotherapeutic response, duration of response to chem- otherapy was used as an integral part of an overall patient otherapy, and overall survival. Secondary analyses were under- management strategy from diagnosis. The cases are detailed in taken to investigate the effects of all of the observed genetic Table 1. Forty-eight patients received combination chemother- alterations, without regard for the
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