<i>c‐Jun</i> amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation programme

Snyder, Eric L.; Sandstrom, Deborah J.; Law, Kenneth; Fiore, Christopher; Sicińska, Ewa; Brito, Joseph; Bailey, D. R. Shackleton; Fletcher, Jonathan A.; Loda, Massimo; Rodig, Scott J.; Cin, Paola Dal; Fletcher, Christopher D.�M.

doi:10.1002/path.2564

Cited by 76 publications

(72 citation statements)

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“…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: 61%

“…Other chromosomes are involved less consistently, such as 1q, 4p, 12q21-22, 13q, and 15q. [5][6][7][8] The 12q15 amplicon consistently contains the MDM2 oncogene, which is considered an essential oncogenic driver in dedifferentiated liposarcoma and the main downregulator of the p53 axis in this tumor type. 1,9 Concomitant amplification of HMGA2, CPM, FRS2, and YEATS4, all located at the same chromosomal region, is invariably present along with MDM2, even though the pathogenetic relevance of these genes in dedifferentiated liposarcoma is not well established.…”

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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: Discussionmentioning

confidence: 61%

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confidence: 99%

STAT6 is amplified in a subset of dedifferentiated liposarcoma

2014

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“…6,15,33 This correlation might suggest a role of JUN in dedifferentiation. 15 However, JUN amplification is also observed in some atypical lipomatous tumors/well-differentiated liposarcomas without any sign of dedifferentiation. In previous reports, a majority of dedifferentiated liposarcomas did not show any amplification of JUN.…”

Section: Discussionmentioning

confidence: 98%

“…However, a systematic link between inhibition of adipocytic differentiation and JUN amplification was not confirmed. 15,16 Our aim was to assess the frequencies of HMGA2, CDK4, and JUN amplification, as well as the prognostic value of these amplifications in a large series of liposarcomas. In particular, we explored the quantitative status of intra-and extraexonic parts of the HMGA2 gene.…”

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confidence: 99%

Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas

et al. 2015

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HMGA2, CDK4, and JUN genes have been described as frequently coamplified with MDM2 in atypical lipomatous tumor, well-differentiated liposarcoma, and dedifferentiated liposarcoma. We studied the frequency of amplification of these genes in a series of 48 dedifferentiated liposarcomas and 68 atypical lipomatous tumors/well-differentiated liposarcomas. We correlated their amplification status with clinicopathological features and outcomes. Histologically, both CDK4 (P = 0.007) and JUN (P = 0.005) amplifications were associated with dedifferentiated liposarcoma, whereas amplification of the proximal parts of HMGA2 (5′-untranslated region (UTR) and exons 1-3) was associated with atypical lipomatous tumor/well-differentiated liposarcoma (P = 0.01). CDK4 amplification was associated with axial tumors. Amplification of 5′-UTR and exons 1-3 of HMGA2 was associated with primary status and grade 1. Shorter overall survival was correlated with: age 464 years (P = 0.03), chemotherapy used in first intent (Po0.001), no surgery (P = 0.003), grade 3 (Po0.001), distant metastasis (Po0.001), node involvement (P = 0.006), and CDK4 amplification (P = 0.07). In multivariate analysis, distant metastasis (HR = 8.8) and grade 3 (HR = 18.2) were associated with shorter overall survival. A shorter recurrence-free survival was associated with dedifferentiated liposarcoma (Po0.001), grade 3 (Po0.001), node involvement (Po0.001), distant metastasis (P = 0.02), recurrent status (P = 0.009), axial location (P = 0.001), and with molecular features such as CDK4 (P = 0.05) and JUN amplification (P = 0.07). Amplification of 5′-UTR and exons 1-3 (P = 0.08) and 3′-UTR (P = 0.01) of HMGA2 were associated with longer recurrence-free survival. Distant metastasis was associated with shorter recurrence-free survival (HR = 5.8) in multivariate analysis. Dedifferentiated liposarcoma type was associated with axial location, grade 3 and recurrent status. In conclusion, we showed that the amplification of HMGA2 was associated with the atypical lipomatous tumor/well-differentiated liposarcoma histological type and a good prognosis, whereas CDK4 and JUN amplifications were associated with dedifferentiated liposarcoma histology and a bad prognosis. In addition, we also provided the first description of the molecular evolution of a well-differentiated liposarcoma into four successive dedifferentiated liposarcoma relapses, which was consistent with our general observations.

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“…Regions of chromosome 12q13-15 are often amplified in welldifferentiated and dedifferentiated liposarcomas, typically involving MDM2, CDK4, and HMGA2, along with several other genes (6,10,12,13); JUN can also be amplified in WDLPS cases that have a dedifferentiated component (14). Further dissection of WDLPS molecular pathogenesis has been greatly impeded by the lack of animal models suitable for experimental analysis.…”

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Aberrant AKT activation drives well-differentiated liposarcoma

Gutiérrez

Snyder

Mariño-Enríquez³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.L iposarcoma is the most common sarcoma of humans, affecting ∼2,000 individuals per year in the United States (1). These tumors are classified into five histopathologic subtypes, with well-differentiated liposarcoma (WDLPS) accounting for ∼50% of cases, and dedifferentiated liposarcoma (DDLPS), a closely related subtype that appears to arise from further malignant progression of WDLPS, accounting for an additional 9% to 18% of cases (1-3). Liposarcomas are generally thought to arise de novo rather than from preexisting benign lesions, and most patients lack recognized causative factors. Although complete surgical resection can be curative, WDLPS often develops in deep anatomic locations, such as the retroperitoneum or mediastinum, where its propensity to enwrap vital structures typically makes complete surgical resection difficult or impossible, leading to high morbidity and mortality rates (1, 4). Radiation and chemotherapy have limited efficacy in the treatment of WDLPS (5, 6). Indeed, there are no systemic therapeutic regimens known to improve survival when complete surgical resection is not feasible, underscoring the need for an improved molecular understanding of WDLPS to stimulate the development of effective targeted therapies.The MDM2-p53 pathway plays a prominent role in WDLPS pathogenesis, with the vast majority of human tumors harboring either MDM2 amplifications or p53 mutations (6-10). Moreover, individuals with germ-line p53 mutations appear to be at increased risk of WDLPS development at a very young age (11).Regions of chromosome 12q13...

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c‐Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation programme

Cited by 76 publications

References 19 publications

STAT6 is amplified in a subset of dedifferentiated liposarcoma

STAT6 is amplified in a subset of dedifferentiated liposarcoma

Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas

Aberrant AKT activation drives well-differentiated liposarcoma

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