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Oncogene. 2016 Sep 22;35(38):5021-32. doi: 10.1038/onc.2016.38. Epub 2016 Mar 7.

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

Jones KB1,2,3, Barrott JJ1,2,3, Xie M4, Haldar M5, Jin H1,2,3, Zhu JF1,2,3, Monument MJ1,3, Mosbruger TL3,6, Langer EM5, Randall RL1,3, Wilson RK4,7,8,9, Cairns BR2,3,10, Ding L4,7,8,9, Capecchi MR5.

Author information

1
Department of Orthopaedics, University of Utah, Salt Lake City, UT, USA.
2
Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
3
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
4
Department of Medicine, Washington University, St Louis, MO, USA.
5
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
6
Department of Bioinformatics, University of Utah, Salt Lake City, UT, USA.
7
McDonnell Genome Institute, Washington University, St Louis, MO, USA.
8
Department of Genetics, Washington University, St Louis, MO, USA.
9
Siteman Cancer Center, Washington University, St Louis, MO, USA.
10
Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT, USA.

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.

PMID:
26947017
PMCID:
PMC5014712
DOI:
10.1038/onc.2016.38
[Indexed for MEDLINE]
Free PMC Article

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