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The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25

Oncogene volume 20, pages 48–57 (2001)Cite this article

Abstract

Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior. Recent cytogenetic studies have identified a recurrent der(17) due to a non-reciprocal t(X;17)(p11.2;q25) in this sarcoma. To define the interval containing the Xp11.2 break, we first performed FISH on ASPS cases using YAC probes for OATL1 (Xp11.23) and OATL2 (Xp11.21), and cosmid probes from the intervening genomic region. This localized the breakpoint to a 160 kb interval. The prime candidate within this previously fully sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinomas. Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25. Amplification of the 5′ portion of cDNAs containing the 3′ portion of TFE3 in two different ASPS cases identified a novel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion) or exon 3 (type 2 fusion). Reverse transcriptase PCR using a forward primer from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12: 9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in most cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matches numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDNA open reading frame encodes a predicted protein of 476 amino acids that contains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to predicted proteins of unknown function in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of TFE3 by the fused ASPL sequences, while retaining the TFE3 DNA-binding domain, implicating transcriptional deregulation in the pathogenesis of this tumor, consistent with the biology of several other translocation-associated sarcomas.

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Acknowledgements

We would like to thank William Gerald, Murray Brennan, Cheryl Coffin, James Neff, Richard Terek, and Henrik Bauer for specimen procurement; Aimée Hamelin, Gisele Colleoni, Marilu Nelson, Patty Cattano, Rebecca Shephard, Jian Liu, and Zhong Chen for technical assistance; Heide Hellebrand for assistance with Xp11 sequence analysis; Debbie MacDougall and Kimberly Christian for assistance with artwork; Kin Kong and Allyne Manzo for photographic work, and Philip H Lieberman for longstanding support. We thank Ad Geurts van Kessel for kindly providing the OATL1 and OATL2 YAC probes. We would also like to thank the following individuals for providing materials (Xp11 probes or ASPS tumor samples) used in earlier stages of this work which did not contribute to the present results: Michael Geraghty, Juan Rosai, and Carol Kruse. The genomic sequence analysis of this region of Xp11.2 deposited in GenBank #AF207550 was performed at the Institute of Molecular Biotechnology, Jena, Germany. ASPS tumor procurement at MSKCC was performed under IRB protocol #90-024, supported by NIH PO1 CA47179. JA Bridge is supported in part by the John A Wiebe Jr Children's Health Care Fund and the Nebraska State Department of Health, LB595. A Meindl is supported by the German Ministry of Research and Education. M Ladanyi is supported in part by NIH PO1 CA47179.

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Authors and Affiliations

  1. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Marc Ladanyi, Man Yee Lui & Cristina R Antonescu

  2. Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Marc Ladanyi

  3. Department of Pathology, CHMG/MMI, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Amber Krause-Boehm & Julia Bridge

  4. Department of Medical Genetics, Ludwig-Maximilians-Universitat, Munchen, Germany

    Alfons Meindl

  5. Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA

    Pedram Argani

  6. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    John H Healey

  7. Department of Orthopedic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan

    Takafumi Ueda & Hideki Yoshikawa

  8. Department of Human Genetics, Huntsman Cancer Institute, University of Utah Medical Center, Salt Lake City, Utah, USA

    Aurelia Meloni-Ehrig

  9. Department of Pathology, British Columbia's Children's Hospital, Vancouver, Canada

    Poul H B Sorensen

  10. Department of Clinical Genetics, University Hospital, Lund, Sweden

    Fredrik Mertens & Nils Mandahl

  11. Center for Human Genetics, University of Leuven, Belgium

    Herman van den Berghe

  12. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Raf Sciot & Paola Dal Cin

  13. Department of Pediatrics, CHMG/MMI, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Julia Bridge

  14. Department of Orthopedic Surgery, CHMG/MMI, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Julia Bridge

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  1. Marc Ladanyi
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Ladanyi, M., Lui, M., Antonescu, C. et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 20, 48–57 (2001). https://doi.org/10.1038/sj.onc.1204074

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