Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy

Barretina, Jordi; Taylor, Barry S.; Banerji, Shantanu; Ramos, Alexis; Lagos-Quintana, Mariana; DeCarolis, Penelope; Shah, Kinjal; Socci, Nicholas D.; Weir, Barbara A.; Ho, Alan L.; Chiang, Derek Y.; Reva, Boris; Mermel, Craig H.; Getz, Gad; Antipin, Yevgenyi; Beroukhim, Rameen; Major, John E.; Hatton, Charlie; Nicoletti, Richard; Hanna, Megan; Sharpe, Ted; Fennell, Tim; Cibulskis, Kristian; Onofrio, Robert C.; Saito, Tsuyoshi; Shukla, Neerav; Lau, Carmen; Nelander, Sven; Silver, Serena J.; Sougnez, Carrie; Viale, Agnès; Winckler, Wendy; Maki, Robert G.; Garraway, Levi A.; Lash, Alex E.; Greulich, Heidi; Root, David E.; Sellers, William R.; Schwartz, Gary K.; Antonescu, Cristina R.; Lander, Eric S.; Varmus, Harold; Ladanyi, Marc; Sander, Chris; Meyerson, Matthew; Singer, Samuel

doi:10.1038/ng.619

Cited by 625 publications

(688 citation statements)

References 51 publications

(37 reference statements)

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“…4 Some structural considerations have been proposed to explain the composition of certain dedifferentiated liposarcoma amplicons; for example, a fragile site located immediately centromeric to the 5 0 end of DDIT3 at 12q14.1 has been proposed to define the centromeric boundary of the CDK4 amplicon, so that chromosomal breakage at this site would have a role in the formation of the non-contiguous amplicons from 12q13-15. 6 Nevertheless, several genes centromeric to this breakpoint are coamplified in around 15% of dedifferentiated liposarcoma (including GLI1, DCTN2, 6,14 and as demonstrated in this report, STAT6), indicating that some cases of dedifferentiated liposarcoma contain either larger amplicons extending over this site, or additional discontinuous amplicons from 12q13.…”

Section: Discussionsupporting

confidence: 68%

“…6,12 Abundant experimental evidence also supports the functional relevance of CDK4 in dedifferentiated liposarcoma. 13,14 Less common genomic events have been variably associated with particular biological features, for example, amplification of JUN and dedifferentiation. 8 The presence of STAT6 amplification demonstrated in this report, combined with the functional evidence of STAT6 dependency in dedifferentiated liposarcoma, 14 highlights the biological and potentially therapeutic relevance of STAT6 in at least a subset of dedifferentiated liposarcoma and provides a basis to explore STAT6-targeting agents 17 as a rational therapeutic strategy in dedifferentiated liposarcoma.…”

Section: Discussionmentioning

confidence: 99%

“…6,10 CDK4 gene amplification and overexpression very likely have an important role in the tumorigenic process in dedifferentiated liposarcoma, but the contribution of other genes in this amplicon has not been explored. 13,14 In addition to providing greater understanding of the pathogenesis of dedifferentiated liposarcoma, the concurrent amplification and overexpression of MDM2 and CDK4 serve as important diagnostic markers that can be detected by immunohistochemistry or FISH. 15 MDM2 and CDK4 also represent attractive potential therapeutic targets-both MDM2 inhibition and CDK4 inhibition have shown promising activity in preclinical models and are being evaluated in clinical trials.…”

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confidence: 99%

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STAT6 is amplified in a subset of dedifferentiated liposarcoma

2014

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A recurrent intrachromosomal rearrangement on chromosome 12q in solitary fibrous tumor leads to the formation of a NAB2-STAT6 fusion oncogene. As a result, nuclear expression of the cytoplasmic transcription factor STAT6 is found in solitary fibrous tumor and serves as a useful diagnostic marker. STAT6 is located in 12q13, a region containing well-characterized oncogenes that are commonly amplified in dedifferentiated liposarcoma; we have previously reported that STAT6 is expressed in a subset of dedifferentiated liposarcoma. The aim of this study was to determine the frequency of STAT6 expression in dedifferentiated liposarcoma and the underlying genetic mechanism. STAT6 protein expression was analyzed by immunohistochemistry in a well-characterized series of 35 previously unpublished cases of dedifferentiated liposarcoma, all with nuclear MDM2 and/or CDK4 expression by immunohistochemistry and/or cytogenetic features of dedifferentiated liposarcoma. FISH for STAT6 was performed in all cases with STAT6 expression, and a subset of control cases without STAT6 expression. In total 4/35 cases (11%) showed STAT6 expression (three with multifocal staining of moderate to strong intensity and one with weak focal staining). FISH demonstrated amplification of STAT6 in all cases positive for STAT6 by immunohistochemistry; in contrast, FISH performed on four STAT6-negative dedifferentiated liposarcomas demonstrated no STAT6 amplification (P ¼ 0.0286). Of the four STAT6 amplified cases, three patients were male and one was female, ranging in age from 51 to 76 years. Tumors were located in the mediastinum (n ¼ 2), paratesticular soft tissue (n ¼ 1), and perirenal soft tissue (n ¼ 1). Three patients received pre-operative chemotherapy þ / À radiation therapy. In conclusion, STAT6 is amplified in a subset of dedifferentiated liposarcoma, resulting in STAT6 protein expression that can be detected by immunohistochemistry and may be a potential pitfall in the differential diagnosis of dedifferentiated liposarcoma and solitary fibrous tumor. These findings suggest a role for STAT6-mediated transcriptional activity in some cases of dedifferentiated liposarcoma and highlight the genomic complexity and heterogeneity of dedifferentiated liposarcoma.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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STAT6 is amplified in a subset of dedifferentiated liposarcoma

2014

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“…These results are consistent with the recent findings of some investigators who reported only rare PIK3CA mutation in SS. 5,23,24 Previous studies have indicated another potential factor in the Akt/mTOR pathway: the activation of receptor tyrosine kinases or cytokine receptors. Epidermal growth factor receptor (EGFR), 14,25,26 insulin-like growth factor-1 receptor (IGF1R), 14,27 and plateletderived growth factor receptor a (PDGFRa) 6,28,29 have been proven responsible for Akt/mTOR pathway activation in SS, and some preclinical studies have lent credence to targeting this pathway.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

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BACKGROUND:The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. METHODS: The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. RESULTS: Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit a (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. CONCLUSIONS: In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

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“…The resulting data should then be functionally validated in vitro and in vivo in normal or fusion gene-harboring MSCs. Using this technology a recent study has identified frequently mutated genes in different subtypes of sarcomas that could constitute new targets for more specific therapies [119]. These frequently mutated genes include TP53 in pleomorphic liposarcomas, NF1 in myxofibrosarcomas and PIK3CA (the catalytic subunit of PI3K) in MLS.…”

Section: Open Questionsmentioning

confidence: 99%

Modeling sarcomagenesis using multipotent mesenchymal stem cells

2011

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Because of their unique properties, multipotent mesenchymal stem cells (MSCs) represent one of the most promising adult stem cells being used worldwide in a wide array of clinical applications. Overall, compelling evidence supports the long-term safety of ex vivo expanded human MSCs, which do not seem to transform spontaneously. However, experimental data reveal a link between MSCs and cancer, and MSCs have been reported to inhibit or promote tumor growth depending on yet undefined conditions. Interestingly, solid evidence based on transgenic mice and genetic intervention of MSCs has placed these cells as the most likely cell of origin for certain sarcomas. This research area is being increasingly explored to develop accurate MSC-based models of sarcomagenesis, which will be undoubtedly valuable in providing a better understanding about the etiology and pathogenesis of mesenchymal cancer, eventually leading to the development of more specific therapies directed against the sarcoma-initiating cell. Unfortunately, still little is known about the mechanisms underlying MSC transformation and further studies are required to develop bona fide sarcoma models based on human MSCs. Here, we comprehensively review the existing MSC-based models of sarcoma and discuss the most common mechanisms leading to tumoral transformation of MSCs and sarcomagenesis.

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Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy

Cited by 625 publications

References 51 publications

STAT6 is amplified in a subset of dedifferentiated liposarcoma

STAT6 is amplified in a subset of dedifferentiated liposarcoma

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Modeling sarcomagenesis using multipotent mesenchymal stem cells

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