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

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

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 n...

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Main Authors: Jones, Kevin B., Barrott, Jared J., Xie, Mingchao, Haldar, Malay, Jin, Huifeng, Zhu, Ju-Fen, Monument, Michael J., Mosbruger, Tim L., Langer, Ellen M., Randall, R. Lor, Wilson, Richard K., Cairns, Bradley R., Ding, Li, Capecchi, Mario R.
Format: Online
Language:English
Published: 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014712/
id pubmed-5014712
recordtype oai_dc
spelling pubmed-50147122016-09-23 The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis Jones, Kevin B. Barrott, Jared J. Xie, Mingchao Haldar, Malay Jin, Huifeng Zhu, Ju-Fen Monument, Michael J. Mosbruger, Tim L. Langer, Ellen M. Randall, R. Lor Wilson, Richard K. Cairns, Bradley R. Ding, Li Capecchi, Mario R. Article 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. 2016-03-07 2016-09-22 /pmc/articles/PMC5014712/ /pubmed/26947017 http://dx.doi.org/10.1038/onc.2016.38 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Jones, Kevin B.
Barrott, Jared J.
Xie, Mingchao
Haldar, Malay
Jin, Huifeng
Zhu, Ju-Fen
Monument, Michael J.
Mosbruger, Tim L.
Langer, Ellen M.
Randall, R. Lor
Wilson, Richard K.
Cairns, Bradley R.
Ding, Li
Capecchi, Mario R.
spellingShingle Jones, Kevin B.
Barrott, Jared J.
Xie, Mingchao
Haldar, Malay
Jin, Huifeng
Zhu, Ju-Fen
Monument, Michael J.
Mosbruger, Tim L.
Langer, Ellen M.
Randall, R. Lor
Wilson, Richard K.
Cairns, Bradley R.
Ding, Li
Capecchi, Mario R.
The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis
author_facet Jones, Kevin B.
Barrott, Jared J.
Xie, Mingchao
Haldar, Malay
Jin, Huifeng
Zhu, Ju-Fen
Monument, Michael J.
Mosbruger, Tim L.
Langer, Ellen M.
Randall, R. Lor
Wilson, Richard K.
Cairns, Bradley R.
Ding, Li
Capecchi, Mario R.
author_sort Jones, Kevin B.
title The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis
title_short The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis
title_full The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis
title_fullStr The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis
title_full_unstemmed The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis
title_sort impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis
description 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.
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014712/
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