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Fluorescent In Situ Hybridization on Isolated Tumor Cell Nuclei: A Sensitive Method for 1p and 19q Deletion Analysis in Paraffin-Embedded Oligodendroglial Tumor Specimens Ellen Gelpi, M.D., Inge M. Ambros, M.D., Peter Birner, M.D., Andrea Luegmayr, Marcus Drlicek, M.D., Ingeborg Fischer, M.D., Reinhold Kleinert, M.D., Hans Maier, M.D., Michael Huemer, M.D., Brigitte Gatterbauer, M.D., Johann Anton, M.D., Karl Rössler, M.D., Herbert Budka, M.D., Peter F. Ambros, Ph.D., Johannes A. Hainfellner, M.D. Institute of Neurology (EG, PB, IF, HB, JAH), Institute of Pathology (PB), and Department of Neurosurgery (BG, KR), University of Vienna, Vienna; Children’s Cancer Research Institute (CCRI), St. Anna Children’s Hospital (IMA, AL, PFA), Vienna; Institute of Pathology, LNK Wagner-Jauregg (MD), Linz; Ludwig Boltzmann Institute of Neurooncology, Kaiser Franz Josef Hospital (MD, IF), Vienna; Institute of Pathology, University of Graz (RK), Graz; Institute of Pathology (HM) and Department of Neurosurgery (JA), University of Innsbruck, Innsbruck; and Department of Neurology, Christian Doppler Hospital (MH), Salzburg, Austria yielded interpretable results in 98.7% for 1p and In oligodendroglial neoplasms, losses of chromo- 92.1% for 19q. Chromosome 1p/19q alterations somal material at 1p and 19q associate with chemo- comprised deletions (1p: 79.5%, 19q: 80%) and im- sensitivity and prolonged survival. Thus, 1p/19q balances (1p: 11.5%, 19q: 12.9%). 1p aberrations testing is increasingly proposed for use in brain were more frequent in oligodendroglioma than in .(001. ؍ tumor diagnosis and prognostic assessment. Fluo- oligoastrocytoma (100% versus 75.9%, P rescent in situ hybridization (FISH) is a classic tech- The frequency of 1p/19q alterations was not signif- nique for investigation of 1p/19q status in paraffin- icantly different in WHO Grade II or Grade III tu- embedded tissues. A major limitation of this mors or in primary and recurrent tumors. We con- method is truncation of tumor cell nuclei compli- clude that FISH on isolated cell nuclei, with cating assessment of hybridization results. In our application of the SIOP Europe Neuroblastoma con- study, we analyzed 1p and 19q status in a series of sensus criteria, is a sensitive method for detection 79 oligodendroglial neoplasms (49 oligodendroglio- and interpretation of 1p and 19q aberrations in mas, 30 oligoastrocytomas, WHO: 57 Grade II, 22 paraffin-embedded tissue specimens of oligoden- Grade III tumors) and controls (gliotic brain tissue: droglial neoplasms. using (4 ؍ diffuse low-grade astrocytoma: n ,4 ؍ n FISH on isolated whole tumor cell nuclei, prepared KEY WORDS: Chemosensitivity, Chromosome 1p, as cytospin preparations, thus bypassing the prob- Fluorescent in situ hybridization, Oligodendroglioma. lem of nuclear truncation. For interpretation of Mod Pathol 2003;16(7):708–715 FISH results, we used consensus criteria as defined by the SIOP—Europe Neuroblastoma Study Group Oligodendroglioma is a morphologically distinct for analysis of peripheral neuroblastic tumors. FISH type of diffuse glioma with variable clinical out- come. In contrast to other types of gliomas, oligo- Copyright © 2003 by The United States and Canadian Academy of dendroglioma is associated with generally good re- Pathology, Inc. VOL. 16, NO. 7, P. 708, 2003 Printed in the U.S.A. sponse to adjuvant therapy (1–3). Various clinical, Date of acceptance: April 1, 2003. radiological and histological features have been This study was supported by the Scientific Funds of the Mayor of Vienna (Project No. 2026) and by CCRI, St. Anna Children’s Hospital Vienna, suggested as prognostic factors. However, none of Vienna, Austria. these parameters predicts reliably response to ad- This study is a cooperative project of the Austrian Neuro-Oncology Net- work (ANN, www.ann.at). juvant therapy (2, 4–11). Authors EG and IMA contributed equally. Recently, DNA losses on chromosomes 1p and Address reprint requests to: Johannes A. Hainfellner, M.D., Institute of Neu- rology, AKH 4J, POB 48, Währinger Gürtel 18-20, A-1097 Vienna, Austria; fax: 19q have been disclosed as common genetic alter- 43-1-40400-5511; e-mail: [email protected]. ations in oligodendroglial neoplasms and much less DOI: 10.1097/01.MP.0000076981.90281.BF frequently in astrocytic neoplasms (12–18). Patients 708 with anaplastic oligodendrogliomas harboring a MATERIALS AND METHODS 1p/19q deletion were shown to have a more favor- A total of 89 paraffin-embedded archival tumor able prognosis and significantly better response to specimens diagnosed as low- and high-grade oligo- chemotherapy as compared with patients with in- dendrogliomas and oligoastrocytomas were col- tact 1p/19q status (1, 17, 19–23). In patients with lected from the five major Austrian neuropatholo- diffuse low-grade gliomas, the 1p/19q status pre- gy/neurooncology units (Vienna, Graz, Innsbruck, dicts prognosis (24) and the predictive value of Salzburg, and Linz). Age of the material ranged 1p/19q status seems more reliable than histology between 2 and 23 years. Control tissues comprised (25). four cases of gliotic brain tissues (neurosurgically Therefore, it has been repeatedly suggested to resected specimens of temporal lobe/Ammon’s amend conventional histological evaluation of ana- horn sclerosis) and 4 cases of diffuse low-grade plastic oligodendroglioma and diffuse low-grade astrocytoma. Histological slides, 4 ␮m in thickness, gliomas with molecular analysis of chromosome were deparaffinized in xylol. Hematoxylin and eo- arms 1p and 19q (1, 3, 9, 19–22, 24–26). As a con- sin (HE) staining and immunohistochemistry for sequence, 1p/19q testing is increasingly proposed glial fibrillary acidic protein (GFAP, polyclonal an- for use in the diagnostic setting. Various methods tibody Z0334; DAKO, Glostrup, Denmark) and epi- are used for 1p/19q deletion analysis, in particular thelial membrane antigen (EMA, monoclonal anti- PCR-based investigations (microsatellite analysis, body E 29, DAKO) were performed according to real-time PCR), comparative genomic hybridiza- standard protocols (35). Immunolabeling was visu- tion, and fluorescent in situ hybridization (FISH) alized with the ChemMate kit (DAKO) and diami- techniques (12, 14, 24, 27–30). Consensus criteria nobenzidine as chromogene. The tumor specimens for assessment and interpretation of analytical re- were reclassified according to WHO 2000 criteria sults in brain tumors are, however, lacking. In con- (36). Accordingly, we categorized those tumors as trast, in peripheral neuroblastic tumors consensus oligodendrogliomas which displayed uniform oli- criteria concerning methodology, evaluation of an- godendroglial morphology, and we categorized alytical results and data interpretation of diagnostic those tumors as oligoastrocytomas that contained 1p testing are well established (31, 32). distinct components with oligodendroglial and as- FISH is a classic technique for molecular cytoge- trocytic differentiation (Fig. 1). We used the anti- netic testing on paraffin-embedded tissues (33). GFAP immunostaining pattern as support for the FISH is not limited by age of material and does not distinction of oligodendroglioma versus oligoastro- require normal autologous or pooled normal refer- cytoma. We considered a ring-like perinuclear ence tissue. Binding of probes can be controlled “gliofibrillary” immunostaining pattern as a char- microscopically. However, one major limitation is acteristic oligodendroglial feature, and we consid- nuclear truncation in tissue sections complicating ered immunolabeling of a fibrillary tumor matrix as evaluation and interpretation of hybridization re- a characteristic feature of an astrocytic component. We used anti-EMA immunostaining for initial sults. To circumvent the problem of signal trunca- screening of the cases to exclude immunoreactive tion, an improved FISH technique, that is, FISH on cell surface structures, a feature that would indicate isolated whole tumor cell nuclei, has been devel- clear cell ependymal neoplasms. oped for chromosome 1p analysis in germ cell tu- For FISH analysis, we marked representative tu- mors. Side-by-side comparison of both methods mor areas on HE stained sections. Corresponding has proven that FISH on isolated tumor cell nuclei areas were identified on the paraffin blocks, and is superior as compared with conventional FISH on core tissue biopsies of 1.5 mm in diameter were tissue sections (32). FISH on isolated tumor cell taken from each block using a Yamshidi needle. The nuclei has meanwhile replaced conventional FISH same procedure was used for sampling of control on tissue sections not only in germ cell tumors but tissues. We prepared isolated cell nuclei of tumor also in other tumor types, most notably peripheral and control samples as described previously (32). In neuroblastic tumors (32, 34). Studies on oligoden- detail, the paraffin-embedded tissue samples and droglial neoplasms have continued to use conven- 1-mm-diameter glass pellets were put into small tional FISH on tissue sections. Therefore, we inves- bags of nylon gauze. The material was then depar- tigated applicability of FISH on isolated tumor cells affinized with xylene for 1.5–3 hours, followed by an on a large series of oligodendroglial neoplasms and ethanol row with decreasing concentrations (100%, assessed FISH results according to consensus crite- 90%, 70%, and 35% for 1 h, respectively). After ria for 1p analysis in peripheral neuroblastic tu- transfer into distilled water, the deparaffinized
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  • Genomic Landscape of Intramedullary Spinal Cord Gliomas Ming Zhang1,10, Rajiv R

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    www.nature.com/scientificreports OPEN Genomic Landscape of Intramedullary Spinal Cord Gliomas Ming Zhang1,10, Rajiv R. Iyer2,10, Tej D. Azad2,3,10, Qing Wang1, Tomas Garzon-Muvdi2,4, Joanna Wang5, Ann Liu2, Peter Burger6, Charles Eberhart6, Fausto J. Rodriguez 6, Daniel M. Sciubba2, Jean-Paul Wolinsky2,7, Ziya Gokaslan2,8, Mari L. Groves2, George I. Jallo2,9* & Chetan Bettegowda1,2* Intramedullary spinal cord tumors (IMSCTs) are rare neoplasms that have limited treatment options and are associated with high rates of morbidity and mortality. To better understand the genetic basis of these tumors we performed whole exome sequencing on 45 tumors and matched germline DNA, including twenty-nine spinal cord ependymomas and sixteen astrocytomas. Though recurrent somatic mutations in IMSCTs were rare, we identifed NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identifed copy number amplifcations in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts (e.g. glioblastoma) did not harbor the canonical mutations associated with their intracranial counterparts. Our fndings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides the framework to begin more biologically based therapeutic strategies. Intramedullary spinal cord tumors (IMSCTs) are a heterogeneous group of rare lesions that can cause signifcant morbidity in both children and adults.