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Polysomy for Chromosomes 1 and 19 Predicts Earlier Recurrence in Anaplastic Oligodendrogliomas with Concurrent 1P/19Q Loss Matija Snuderl,1 April F

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Polysomy for Chromosomes 1 and 19 Predicts Earlier Recurrence in Anaplastic Oligodendrogliomas with Concurrent 1P/19Q Loss Matija Snuderl,1 April F Published OnlineFirst October 6, 2009; DOI: 10.1158/1078-0432.CCR-09-0867 Published Online First on October 6, 2009 as 10.1158/1078-0432.CCR-09-0867 Imaging, Diagnosis, Prognosis Polysomy for Chromosomes 1 and 19 Predicts Earlier Recurrence in Anaplastic Oligodendrogliomas with Concurrent 1p/19q Loss Matija Snuderl,1 April F. Eichler,2 Keith L. Ligon,4 Quynh U. Vu,1 Michael Silver,3 Rebecca A. Betensky,5 Azra H. Ligon,4 Patrick Y. Wen,6 David N. Louis,1 and A. John Iafrate1 Abstract Purpose: Loss of chromosome arms 1p and 19q is a molecular feature of oligodendrog- lial tumors characterized by responsiveness to chemotherapy and a favorable progno- sis. The purpose of this study was to evaluate the prognostic significance of polysomy of chromosomes 1 and 19 in the setting of 1p/19q codeletion. Experimental Design: We analyzed 64 anaplastic oligodendrogliomas with 1p/19q loss or maintenance diagnosed at Massachusetts General Hospital and Brigham and Women's Hospital from 1996 to 2005; fluorescence in situ hybridization for 1p/19q and Ki-67 immunohistochemistry was done. Polysomy was defined as more than two 1q and 19p signals in >30% of the cells with concurrent 1p/19q deletion. Tumors were divided into groups based on their 1p/19q status and compared for progression- free survival, overall survival, and 5-year survival probabilities. Results: Forty-six tumors (72%) in our cohort had 1p/19q loss and 18 (28%) had 1p/19q maintenance. Of those with loss, 19 (41%) had concurrent polysomy and 27 (59%) lacked polysomy. In agreement with previous studies, the group of anaplastic oligoden- drogliomas with 1p/19q loss had significantly better progression-free survival and over- all survival than anaplastic oligodendrogliomas with 1p/19q maintenance (P = 0.0009 and P < 0.0003, respectively). Among anaplastic oligodendrogliomas with 1p/19q loss, those with polysomy showed shorter progression-free survival than those with 1p/19q loss without polysomy (P = 0.0048). Overall survival was similar in tumors with and without polysomy. The Ki-67 labeling index was not associated with polysomy and did not have prognostic significance. Conclusion: The presence of polysomy in anaplastic oligodendrogliomas with deletion of 1p/19q is a marker of earlier recurrence. (Clin Cancer Res 2009;15(20):OF1–8) Oligodendrogliomas represent ∼2% to 3% of adult primary lomustine, and vincristine (7–10), and to temozolomide CNS neoplasms and 7% to 10% of all gliomas (1–3). Loss of (11, 12), as well as to radiotherapy (13). 1p/19q status thus chromosomal arms 1p and 19q is commonly observed in glial represents a reliable marker of biological behavior, and testing tumors withan oligodendroglioma component, including for 1p/19q loss is now considered standard of care (14, 15). ∼80% of oligodendrogliomas, 50% to 60% of anaplastic oligo- Nonetheless, despite the fact that most anaplastic oligoden- dendrogliomas, and 30% to 50% of oligoastrocytomas and drogliomas with1p/19q codeletion respond to therapy,most anaplastic oligoastrocytomas (3–6). Numerous studies have recur and require additional treatment. Therefore, markers to shown an association between 1p/19q codeletion and a favor- detect tumors with higher risk for early recurrence within the able response to chemotherapy, including to procarbazine, 1p/19q codeleted population would be clinically useful. In this regard, molecular markers that can potentially identify higher-risk tumors within subgroups defined by 1p/19q loss Authors' Affiliations: 1Pathology Service, 2Pappas Center for Neuro-oncology, and maintenance have been proposed (10). and 3Biostatistics Center, Massachusetts General Hospital; 4Department of Although numerous studies have confirmed the significance Pathology, Brigham and Women's Hospital; 5Department of Biostatistics, of 1p/19q loss as a predictor of response to therapy in ana- Harvard School of Public Health; and 6Center for Neuro-oncology, Dana plastic oligodendroglioma, the genes responsible for tumori- Farber/Brigham and Women's Cancer Center, Boston, Massachusetts genesis and/or therapeutic sensitivity have not been identified Received 4/6/09; revised 7/21/09; accepted 8/3/09; published OnlineFirst 10/6/09. – The costs of publication of this article were defrayed in part by the payment of (16 22). The exact mechanism of the loss has also been enig- page charges. This article must therefore be hereby marked advertisement matic, but recent studies suggest that loss of 1p and 19q is in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. mediated by formation of a balanced whole arm transloca- Requests for reprints: John Iafrate, Pathology Service, Massachusetts tion involving chromosomes 1 and 19, with subsequent loss General Hospital, 55 Fruit Street, Wrn 501 Boston, MA 02114-2698. Phone: 617-726-0166; Fax: 617-726-2365; E-mail: [email protected]. of the derivative chromosome der(1;19)(p10;q10) and main- F 2009 American Association for Cancer Research. tenance of the der(1;19)(q10;p10) (23, 24). In clinical prac- doi:10.1158/1078-0432.CCR-09-0867 tice, PCR and fluorescence in situ hybridization (FISH) are the www.aacrjournals.org OF1 Clin Cancer Res 2009;15(20) October 15, 2009 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst October 6, 2009; DOI: 10.1158/1078-0432.CCR-09-0867 Imaging, Diagnosis, Prognosis Progression-free survival was defined as the time from diagnosis to Translational Relevance progression as defined above or thetime to deathif deathoccurred without progression. Overall survival was defined as the time from 1p/19q chromosomal loss is present in anaplastic the initial diagnosis to death. oligodendrogliomas with improved response to Histopathology and immunohistochemistry. All studies were done on chemotherapy and improved survival. We report formalin-fixed, paraffin-embedded tissues. Sections were stained with that chromosomal polysomy in anaplastic oligo- H&E and were reviewed, and diagnosis and grade were confirmed by two neuropathologists independently (M. Snuderl; K.L. Ligon) using dendrogliomas with 1p/19q loss identifies tumors WHO 2007 criteria (3). Low-grade oligodendrogliomas and tumors with a high-risk potential for recurrence. Polysomy withastrocytic components were excluded. does not correlate with Ki-67 staining and thus A representative paraffin block was selected for immunohistochemi- seems independent of proliferation activity. Poly- cal studies. A rabbit monoclonal anti–Ki-67 IgG antibody (clone 30-9; somy assessment, as a novel prognostic marker, Ventana Medical Systems), supplied and prediluted by the manufactur- can be rapidly introduced into the clinical practice er, was used for the study. Immunohistochemistry was done on Bench- because fluorescence in situ hybridization is one of Mark XT automated tissue staining systems (Ventana Medical Systems, the most common molecular methods for 1p/19q Inc.) using validated protocols and tonsil as a positive control. Tissues status evaluation. were counter stained with hematoxylin. In the areas of the highest expression, 500 cells were counted (40× objective), and a labeling index was calculated as the percentage of positive tumor cells. FISH. FISH was done for 1p and 19q loss, as described previously most commonly used methods and have been considered to (26). Briefly, 5-μm sections of formalin-fixed, paraffin-embedded tu- generally provide equivalent prognostic information. Howev- mor material were prepared, and an H&E section was reviewed to select er, studies using FISH have noted that, in addition to the loss regions for hybridization that contain most tumor cells. Two separate of 1p and 19q, a subset of tumors possess additional copies dual-color FISH assays were done; one slide used Bacterial Artificial of these chromosomes (5, 25) and that this was more com- Chromosome probes RP11-558F24 (chromosome 1p; labeled orange) mon in anaplastic and recurrent tumors. Our anecdotal obser- and RP11-45903 (chromosome 1q; labeled green), and the second slide vations of occasional cases of rapidly progressing anaplastic used RP11-75H6 (chromosome 19p; labeled green) and RP11-293G10 (chromosome 19q; labeled orange). Signal quantitation of 100 nuclei oligodendroglioma with1p/19q loss and extra copies of 1p was used to generate a 1p/1q ratio and a 19q/19p ratio. The total num- and 19q using FISH, prompted us to explore polysomy in a ber of signals was counted, and a ratio of 1p:1q (or 19q:19p) of <0.75 larger cohort of anaplastic oligodendrogliomas. was diagnosed as loss and ≥0.75 as maintenance, which are the scoring In this study, we have quantitated 1p and 19q signals by parameters also used in our clinical practice. The tumor was considered FISH in a cohort of anaplastic oligodendroglioma to detect to have polysomy if ≥30% of nuclei showed three or more signals for polysomy of chromosomes 1 and 19. Progression-free and 1q and 19p. overall survival was determined for tumors withand without Statistics. Based on FISH results, patients were divided into the fol- loss of 1p/19q; within the codeleted group, we compared lowing groups for survival analyses: (a) loss of 1p/19q withpolysomy, tumors withand withoutpolysomy. To analyze if polysomy (b) loss of 1p/19q without polysomy, and (c) maintenance of 1p/19q. is a surrogate marker for increased mitotic activity, we also Groups were then compared for progression-free survival, overall sur- compared proliferation indices in 1p/19q codeleted anaplastic vival,
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