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Positive Clear Cell Sarcoma of Soft Tissue Cell Lines Reveals Characteristic Up-Regulation of Potential New Marker Genes Including ERBB3

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Positive Clear Cell Sarcoma of Soft Tissue Cell Lines Reveals Characteristic Up-Regulation of Potential New Marker Genes Including ERBB3 [CANCER RESEARCH 64, 3395–3405, May 15, 2004] Expression Profiling of t(12;22) Positive Clear Cell Sarcoma of Soft Tissue Cell Lines Reveals Characteristic Up-Regulation of Potential New Marker Genes Including ERBB3 Karl-Ludwig Schaefer,1 Kristin Brachwitz,1 Daniel H. Wai,2 Yvonne Braun,1 Raihanatou Diallo,1 Eberhard Korsching,2 Martin Eisenacher,2 Reinhard Voss,3 Frans van Valen,4 Claudia Baer,5 Barbara Selle,5 Laura Spahn,6 Shuen-Kuei Liao,7 Kevin A. W. Lee,8 Pancras C. W. Hogendoorn,9 Guido Reifenberger,10 Helmut E. Gabbert,1 and Christopher Poremba1 1Institute of Pathology, Heinrich-Heine-University, Dusseldorf, Germany; 2Gerhard-Domagk-Institute of Pathology, 3Institute of Arteriosclerosis Research, and 4Laboratory for Experimental Orthopaedic Research, Department of Orthopaedic Surgery, University of Muenster, Muenster, Germany; 5Department of Hematology and Oncology, University Children’s Hospital of Heidelberg, Heidelberg, Germany; 6Children’s Cancer Research Institute, St. Anna Kinderspital, Vienna, Austria; 7Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China; 8Department of Biology, Hong Kong University of Science and Technology, Kowloon, Hong Kong S.A.R. China; 9Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; and 10Department of Neuropathology, Heinrich-Heine-University, Dusseldorf, Germany ABSTRACT INTRODUCTION Clear cell sarcoma of soft tissue (CCSST), also known as malignant Clear cell sarcoma of soft tissue (CCSST) is a rare lesion, which is melanoma of soft parts, represents a rare lesion of the musculoskeletal characterized by melanocytic differentiation and accounts for ϳ1% of system usually affecting adolescents and young adults. CCSST is typified all malignancies of the musculoskeletal system (1–3). CCSST, which by a chromosomal t(12;22)(q13;q12) translocation resulting in a fusion usually affects adolescents and young adults, is commonly associated between the Ewing sarcoma gene (EWSR1) and activating transcription with tendons and aponeuroses and is believed to be derived from factor 1 (ATF1), of which the activity in nontransformed cells is regulated neuroectodermal tissues (4). The tumor cells are typified by the by cyclic AMP. Our aim was to identify critical differentially expressed presence of a balanced t(12;22)(q13;q12) rearrangement: the result is genes in CCSST tumor cells in comparison with other solid tumors a fusion between the Ewing sarcoma gene (EWSR1) and activating affecting children and young adults to better understand signaling path- transcription factor 1 (ATF1), which permits the expression of an ways regulating specific features of the development and progression of EWS-ATF1 oncoprotein (5). ATF1, along with cyclic AMP (cAMP)- this tumor entity. We applied Affymetrix Human Genome U95Av2 oligo- responsive element binding protein and modulator (CREM), comprise nucleotide microarrays representing ϳ12,000 genes to generate the ex- pression profiles of the CCSST cell lines GG-62, DTC-1, KAO, MST2, a bZIP subfamily of transcription factors, which regulate gene expres- MST3, and Su-CC-S1 in comparison with 8 neuroblastoma, 7 Ewing sion via homo- or heterodimeric binding to cAMP response elements tumor, and 6 osteosarcoma cell lines. Subsequent hierarchical clustering (CREs; Ref. 6). EWS-ATF1 activates transcription independently of of microarray data clearly separated all four of the tumor types from each cAMP induction due to a partial deletion of the ATF1 kinase-induc- other and identified differentially expressed transcripts, which are char- ible domain (7); moreover, the EWS-ATF1 fusion protein has been acteristically up-regulated in CCSST. Statistical analysis revealed a group shown to act as a potent activator of several cAMP-inducible promot- of 331 probe sets, representing ϳ300 significant (P < 0.001) differentially ers (8, 9). Therefore, EWS-ATF1 may exert its oncogenic properties regulated genes, which clearly discriminated between the CCSST and via the induction or deregulation of genes that govern transcription, other tumor samples. Besides genes that were already known to be highly cell division, and signal transduction. expressed in CCSST, like S100A11 (S100 protein) or MITF (microphthal- According to their histological appearance CCSST can resemble mia-associated transcription factor), this group shows an obvious portion other malignant mesenchymal tumors of childhood and adolescence. of genes that are involved in cyclic AMP response or regulation, in Immunostaining for S100 and especially markers for melanocytic pigmentation processes, or in neuronal structure and signaling. Compar- differentiation (including melan-A, the microphthalmia-associated ison with other expression profile analyses on neuroectodermal childhood transcription factor, or the melanosomal matrix protein Pmel17, which tumors confirms the high robustness of this strategy to characterize tumor is detected by HMB-45 monoclonal antibodies) is usually included in entities based on their gene expression. We found the avian erythroblastic the examination of tumor biopsies to arrive at a reliable diagnosis leukemia viral oncogene homologue 3 (ERBB3) to be one of the most dramatically up-regulated genes in CCSST. Quantitative real-time PCR (10). Because cutaneous, deeply invasive spindle-cell melanomas that and Northern blot analysis verified the mRNA abundance and confirmed lack a demonstrable primary tumor and CCSST share a broad panel the absence of the inhibitory transcript variant of this gene. The protein of these histological and immunohistologic features, the distinction of product of the member of the epidermal growth factor receptor family these two lesions should include proving the presence or absence of ERBB3 could be shown to be highly present in all of the CCSST cell lines the t(12;22) translocation, which is only found in CCSST (11, 12). investigated, as well as in 18 of 20 primary tumor biopsies. In conclusion, Besides the diagnosis, the treatment of CCSST patients may rep- our data demonstrate new aspects of the phenotype and the biological resent a serious challenge to the physician. The tumor often presents behavior of CCSST and reveal ERBB3 to be a useful diagnostic marker. as a painless, slowly growing mass, which can radiologically be mistaken as a benign process (13, 14). Nevertheless, CCSST repre- Received 3/28/03; revised 2/9/04; accepted 3/4/04. sents a fully malignant neoplasm with the tendency to metastasize to Grant support: Forschungskommission der Medizinischen Fakultaet Duesseldorf regional lymph nodes and the lung, and the likelihood of local or (9772 190), Elterninitiative Kinderkrebsklinik e.V. Duesseldorf, IMF Muenster (SC 21 01 22), the Aktion fu¨r krebskranke Kinder e.V., Heidelberg, Germany, the National Science distant recurrences is high as evidenced by 5-year survival rates Council of the Republic of China (NSC-85–0412-B182–096 and NSC88–2314-13–182- of ϳ50%. Only a few data are available on the clinical management 049), and the German Research Foundation (DFG) (Po 529/5-1). of this rare soft tissue lesion. One major problem in the treatment of The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with CCSST is the resistance of this entity to chemotherapeutic drugs, 18 U.S.C. Section 1734 solely to indicate this fact. which in other soft tissue tumors are reported to be at least partially Requests for reprints: Christopher Poremba, Institute of Pathology, Heinrich-Heine- University Duesseldorf, Germany, Moorenstrasse 5, 40225 Duesseldorf, Germany. Phone: effective (14, 15). 49-211-8118492; Fax: 49-211-8118353; E-mail: [email protected]. To additionally understand the processes that control this rare, 3395 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2004 American Association for Cancer Research. MICROARRAY ANALYSIS OF CLEAR CELL SARCOMA slowly growing but highly malignant cancer type and obtain new MST2 was derived from a 60-year-old Taiwanese male who had noted a insights for new potentially diagnostic markers or therapeutic targets, slowly growing mass at his right knee for 5 years. Because of aggravated we report here the microarray analysis of 6 CCSST cell lines and 21 pain, the tumor (measuring 6 cm ϫ 4cmϫ 3 cm) was excised in May 1994. cell lines derived from other solid tumors affecting children and The initial histopathological diagnosis was synovial sarcoma. Magnetic young adults. resonance imaging performed 2 weeks after initial surgery revealed resid- Using this powerful tool (16, 17) in combination with statistical ual tumor. After radical excision, histopathological diagnosis at a different analysis we were able to identify characteristic multigene expression department revealed a spindle cell neoplasm with tumor cells exhibiting focally clear cytoplasm, large nuclei with prominent nucleoli, and melanin patterns, which point to new regulatory mechanisms, cellular func- granules. Immunohistochemically, the tumor cells were positive for HMB- tions, and the molecular biological phenotype of CCSST. 45. The diagnosis was changed to CCSST. In November 1994, after radical surgery followed by two cycles of chemotherapy using the British Colum- MATERIALS AND METHODS bia Drug Treatment Program regimen {carmustine [1,3-bis(2-chloroethyl)- 1-nitrosourea], cisplatin, dacarbazine [5-(3,3-dimethyl-1-triazeno)-imidaz- Clinical
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