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Fusion of the NH2-Terminal Domain of the Basic Helix-Loop-Helix Protein TCF12 to TEC in Extraskeletal Myxoid Chondrosarcoma with Translocation T(9;15)(Q22;Q21)1

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Fusion of the NH2-Terminal Domain of the Basic Helix-Loop-Helix Protein TCF12 to TEC in Extraskeletal Myxoid Chondrosarcoma with Translocation T(9;15)(Q22;Q21)1 [CANCER RESEARCH 60, 6832–6835, December 15, 2000] Advances in Brief Fusion of the NH2-Terminal Domain of the Basic Helix-Loop-Helix Protein TCF12 to TEC in Extraskeletal Myxoid Chondrosarcoma with Translocation t(9;15)(q22;q21)1 Helene Sjo¨gren, Barbro Wedell, Jeanne M. Meis Kindblom, Lars-Gunnar Kindblom, and Go¨ran Stenman2 Lundberg Laboratory for Cancer Research, Department of Pathology, Go¨teborg University, SE-413 45 Go¨teborg, Sweden Abstract domain of TLS/FUS is linked to the entire coding region of the transcription factor CHOP as a result of a t(12;16)(q13;p11) (reviewed Extraskeletal myxoid chondrosarcomas (EMCs) are characterized by in Ref. 9). Thus, the NH -terminal transactivation domains of the recurrent t(9;22) or t(9;17) translocations resulting in fusions of the 2 EWS family of RNA binding proteins are regularly fusion partners of NH2-terminal transactivation domains of EWS or TAF2N to the entire TEC protein. We report here an EMC with a novel translocation t(9; various transcription factors in sarcomas, suggesting that they might 15)(q22;q21) and a third type of TEC-containing fusion gene. The chi- have important oncogenic properties. Indeed, it has been shown that meric transcript encodes a protein in which the first 108 amino acids of EWS-FLI1, TAF2N-FLI1, TLS-CHOP, and EWS-CHOP can trans- the NH2-terminus of the basic helix-loop-helix (bHLH) protein TCF12 is form 3T3 cells and that the transforming activity is dependent on linked to the entire TEC protein. The translocation separates the NH2- the presence of the NH2-terminal parts of EWS, TAF2N, and TLS terminal domain of TCF12 from the bHLH domain as well as from a (10–12). potential leucine zipper domain located immediately downstream of the We report here a third type of TEC-containing fusion gene occur- breakpoint. These results demonstrate that the NH2-terminal transactiva- ring in an EMC with a novel translocation t(9;15)(q22;q21). The tion domains of EWS or TAF2N are not unique in their ability to convert chimeric transcript encodes a protein in which the NH -terminal the TEC protein into an oncogenically active fusion protein, and that they 2 domain of the bHLH protein TCF12 is linked to the entire TEC may be replaced by a domain from a bHLH protein that presumably endows the fusion protein with similar functions. protein. These findings indicate that the NH2-terminal domains of EWS or TAF2N are not unique in their ability to convert the TEC protein into an oncogenically active fusion protein. Introduction Previous cytogenetic studies have revealed two recurrent chromo- Materials and Methods some translocations in EMC,3 i.e., a t(9;22)(q22;q12) and a t(9; Tumor Material and Cytogenetic Analysis. Fresh tumor tissue was ob- 17)(q22;q11) (1–5). Both translocations result in fusion genes in tained from a 71-year-old man who had a 2-year history of a slowly growing Ј which the TEC gene at 9q22 is the 3 partner gene (3–7). TEC encodes right thigh mass. The tumor arose in the vastus lateralis and measured 25 cm an orphan nuclear receptor belonging to the steroid/thyroid receptor in greatest dimension on computed tomography and magnetic resonance im- gene super family. In the t(9;22), TEC is fused to the EWS gene at aging. Two additional tumor nodules, 3 and 4 cm each, were found in the 22q12 (6, 7). The resulting fusion protein consists of the NH2-terminal pectoralis major muscles. Fine-needle aspiration of the thigh mass revealed a transactivation domain of EWS linked to the entire TEC protein. sarcoma. The primary tumor was radically excised, and the chest wall metas- EWS, which was originally identified as the target gene rearranged in tases were excised locally. The patient received no adjuvant treatment; he Ewing’s sarcoma with t(11;22)(q24;q12), encodes a putative RNA developed skeletal and soft tissue metastases and died 10 months after diag- binding protein containing a central RNA binding RNP-1 motif (8). In nosis. Macroscopically, the primary tumor was multinodular, solid, gray-white, the variant translocation t(9;17), the EWS-related gene TAF2N at and partly hemorrhagic. Histologically, it was characterized by a predomi- 17q11 has been shown recently to replace EWS as a fusion partner to nantly solid growth of relatively small, uniform cells with minimal cytoplasm; TEC (3–5). oval, reniform, and clefted nuclei; finely distributed chromatin; and small The NH2-terminal domain of EWS is also fused to a variety of nucleoli (Fig. 1). Mitotic activity was low. There was abundant extracellular transcription factors in several other sarcomas, including Ewing’s proteinaceous material and a scant amount of basophilic myxoid matrix. The sarcoma, clear cell sarcoma of tendons and aponeuroses, and desmo- differential diagnosis was broad. The negative panel of immunostains (epithe- plastic small round cell tumor (reviewed in Ref. 9). A third member lial, melanocytic, lymphoid, myeloid, muscular, and primitive neuroectoder- of the EWS and TAF2N gene family, TLS/FUS, is also involved in a mal markers), strong vimentin positivity, and certain ultrastructural features (abundant mitochondria, glycogen deposits, cytoplasmic projections, irregu- similar gene fusion in myxoid liposarcoma in which the NH2-terminal larly clefted nuclei, and prominent nucleoli) were compatible with the diag- nosis of cellular-solid variant of EMC, as described previously (13). The Received 7/26/00; accepted 10/26/00. cytogenetic and molecular genetic findings (see below) as well as the ultra- 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 structural detection of scattered neurosecretory granules in the tumor cells 18 U.S.C. Section 1734 solely to indicate this fact. were also consistent with this diagnosis (14). 1 This work was supported by the Swedish Cancer Society, the IngaBritt and Arne Primary cultures were established from a fresh, unfixed specimen of the Lundberg Research Foundation, King Gustav V Jubile´e Clinic Cancer Research Founda- primary tumor as described previously (3). Chromosome preparations were tion, and the Sahlgrenska University Hospital Foundations. 2 To whom requests for reprints should be addressed, at Lundberg Laboratory for made from exponentially growing primary cultures, and these were subse- Cancer Research, Department of Pathology, Go¨teborg University, Sahlgrenska University quently G-banded and analyzed using standard procedures. Hospital, SE-413 45 Go¨teborg, Sweden. Phone: 46-31-3422922; Fax: 46-31-820525; SKY Analysis. Three- to five-day-old slides were treated with a pepsin E-mail: [email protected]. solution (12 ␮g/ml) for 4 min prior to hybridization. The SkyPaint probe used 3 The abbreviations used are: EMC, extraskeletal myxoid chondrosarcoma; bHLH, basic helix-loop-helix protein; RT-PCR, reverse transcription-PCR; SKY, spectral karyo- contains a cocktail of 24 differentially labeled, chromosome-specific painting typing; DAPI, 4Ј,6Ј-diamidino-2Ј-phenylindole dihydrochloride. probes (ASI-Applied Spectral Imaging, Ltd., Migdal HaЈEmek, Israel). The 6832 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2000 American Association for Cancer Research. TCF12-TEC GENE FUSION IN EMC Applied Biosystems) using the BigDye Terminator Cycle Sequencing Ready Reaction kit (Perkin-Elmer Applied Biosystems). The resulting sequences were analyzed using basic local alignment search tool (BLAST) searches (National Center for Biotechnology Information). Results and Discussion In an effort to identify novel chromosome translocations and fusion genes in EMC, we have cytogenetically analyzed a series of new EMC cases including a tumor with a novel translocation t(9;15). The karyo- type of this tumor was 48, X, ϪY, t(9;15)(q22;q21), ϩ12, ϩder(15)t(9;15)(q22;q21), ϩ19 [8] (Fig. 2A). There were also six cells with a normal karyotype. To confirm the t(9;15) and to search for possible cryptic rearrangements, we also performed SKY analysis. Detailed analysis of the SKY and DAPI band images from eight metaphases corroborated the t(9;15) and the duplication of the der(15) Fig. 1. Solid proliferation of small, uniform tumor cells with indistinct cytoplasm and marker as well as the presence of extra copies of chromosomes 12 and rounded, sometimes folded nuclei with evenly distributed chromatin and distinct nucleoli, 19 (Fig. 2B). No cryptic rearrangements were detected in any of the a picture compatible with the cellular-solid variant of EMC. cells analyzed. To the best of our knowledge, this is the first descrip- tion of a reciprocal t(9;15)(q22;q21) translocation in EMC, raising the conditions for hybridization, posthybridization washes, and detection were possibility that it represents a third variant translocation. essentially as recommended by the manufacturer. Chromosomes were coun- Interestingly, there are two other known cases of EMC with in- terstained with DAPI containing an antifade solution. Image acquisition was volvement of chromosomes 9 and 15; one case with a t(9;22;15)(q31; achieved with the SpectraCube system (ASI) mounted on a Zeiss Axioplan 2 q12.2;q25) (Ref. 16), and another with a t(9;17;15)(q22;q11.2;q22) Imaging microscope equipped with a custom designed optical filter cube (Ref. 17). The latter case most likely represents a variant translocation (SKY-1; Chroma Technology, Brattleboro, VT) and a DAPI filter (15). Anal- of the recently described t(9;17)(q22;q12) resulting in a TAF2N-TEC ysis of spectral images was performed using the SkyView software (ASI). fusion gene, whereas the former is probably a variant of the classical RNA Isolation, RT-PCR, and Nucleotide Sequence Analyses. Total t(9;22)(q22;12), resulting in an EWS-TEC fusion gene.
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