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The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis

Oncogene volume 35, pages 5021–5032 (2016)Cite this article

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Abstract

Synovial sarcomas are aggressive soft-tissue malignancies that express chromosomal translocation-generated fusion genes, SS18-SSX1 or SS18-SSX2 in most cases. Here, we report a mouse sarcoma model expressing SS18-SSX1, complementing our prior model expressing SS18-SSX2. Exome sequencing identified no recurrent secondary mutations in tumors of either genotype. Most of the few mutations identified in single tumors were present in genes that were minimally or not expressed in any of the tumors. Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes. Thus, by fusion oncogene coding sequence alone, SS18-SSX1 and SS18-SSX2 can each drive comparable synovial sarcomagenesis, independent from other genetic drivers. SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences overall. In direct tumorigenesis comparisons, SS18-SSX2 was slightly more sarcomagenic than SS18-SSX1, but equivalent in its generation of biphasic histologic features. Meta-analysis of human synovial sarcoma patient series identified two tumor–gentoype–phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. This suggests that the translocated locus may drive genotype–phenotype differences more than the coding sequence of the fusion gene created. Two possible roles for native SSX2 in synovial sarcomagenesis are explored. Thus, even specific partial failures of mouse genetic modeling can be instructive to human tumor biology.

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Acknowledgements

We thank Matt Hockin for provision of the TATCre and Marc Ladanyi, Louis Guillo, Jean-Michel Coindre, Fernanda Amary, Alessandro Gronchi, Ira Koković, Satoshi Takenaka and Takafumi Ueda for sharing raw data from their previously published patient series. This work was directly supported by the Paul Nabil Bustany Memorial Fund for Synovial Sarcoma Research and the Damon Runyon Cancer Research Foundation to KBJ, National Cancer Institute/National Institutes of Health (NCI/NIH) grant R01CA180006 to LD and National Human Genome Research Institute/NIH grants U01HG006517 to LD and U54HG003079 to RKW. KBJ received additional career development support from NCI/NIH K08CA138764. This work was also partly supported by P30CA042014 from the National Cancer Institute and the Huntsman Cancer Foundation.

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Authors and Affiliations

  1. Department of Orthopaedics, University of Utah, Salt Lake City, UT, USA

    K B Jones, J J Barrott, H Jin, J-F Zhu, M J Monument & R L Randall

  2. Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA

    K B Jones, J J Barrott, H Jin, J-F Zhu & B R Cairns

  3. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    K B Jones, J J Barrott, H Jin, J-F Zhu, M J Monument, T L Mosbruger, R L Randall & B R Cairns

  4. Department of Medicine, Washington University, St Louis, MO, USA

    M Xie, R K Wilson & L Ding

  5. Department of Human Genetics, University of Utah, Salt Lake City, UT, USA

    M Haldar, E M Langer & M R Capecchi

  6. Department of Bioinformatics, University of Utah, Salt Lake City, UT, USA

    T L Mosbruger

  7. McDonnell Genome Institute, Washington University, St Louis, MO, USA

    R K Wilson & L Ding

  8. Department of Genetics, Washington University, St Louis, MO, USA

    R K Wilson & L Ding

  9. Siteman Cancer Center, Washington University, St Louis, MO, USA

    R K Wilson & L Ding

  10. Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT, USA

    B R Cairns

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  1. K B Jones
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Correspondence to K B Jones.

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Jones, K., Barrott, J., Xie, M. et al. The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis. Oncogene 35, 5021–5032 (2016). https://doi.org/10.1038/onc.2016.38

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