MDM2 Amplified Sarcomas: A Literature Review

Sciot, Raf

doi:10.3390/diagnostics11030496

Cited by 66 publications

(64 citation statements)

References 40 publications

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“…MDM2 is the main driver gene with the 12q amplicon. MDM2 binds to p53 and negatively regulates it by preventing nuclear translocation and transcription and by promoting its degradation via an E3 ubiquitin ligase [ 16 ]. CDK4 encodes a 33-kD protein that is a key factor in the regulation of the G1-S translation of the cell cycle.…”

Section: Pathogenesismentioning

confidence: 99%

Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives

Nishio

Nakayama

Nabeshima

et al. 2021

JCM

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Dedifferentiated liposarcoma (DDL) is defined as the transition from well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) to non-lipogenic sarcoma, which arises mostly in the retroperitoneum and deep soft tissue of proximal extremities. It is characterized by a supernumerary ring and giant marker chromosomes, both of which contain amplified sequences of 12q13-15 including murinedouble minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) cell cycle oncogenes. Detection of MDM2 (and/or CDK4) amplification serves to distinguish DDL from other undifferentiated sarcomas. Recently, CTDSP1/2-DNM3OS fusion genes have been identified in a subset of DDL. However, the genetic events associated with dedifferentiation of WDL/ALT remain to be clarified. The standard treatment for localized DDL is surgery, with or without radiotherapy. In advanced disease, the standard first-line therapy is an anthracycline-based regimen, with either single-agent anthracycline or anthracycline in combination with the alkylating agent ifosfamide. Unfortunately, this regimen has not necessarily led to a satisfactory clinical outcome. Recent advances in the understanding of the pathogenesis of DDL may allow for the development of more-effective innovative therapeutic strategies. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology and treatment of DDL.

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Section: Pathogenesismentioning

confidence: 99%

Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives

Nishio

Nakayama

Nabeshima

et al. 2021

JCM

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“…All of the chromosomal locations and genes for those involved with hemizygous deletions are in Supplementary Table S1 . The genomic amplification of the MDM2 gene in this tumor, as confirmed by IHC, might be one of the primary drivers [ 15 ]. MDM2 amplification was observed in 18.6% of sarcoma cases based on the TCGA database (PanCancer Atlas).…”

Section: Discussionmentioning

confidence: 99%

“…MDM2 amplification was observed in 18.6% of sarcoma cases based on the TCGA database (PanCancer Atlas). Notably, MDM2 amplification is most common in well-differentiated liposarcoma/atypical lipomatous tumors, dedifferentiated liposarcoma, intimal sarcoma, and low-grade osteosarcoma [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Transient Response of Olaparib on Pulmonary Artery Sarcoma Harboring Multiple Homologous Recombinant Repair Gene Alterations

Tan

2021

JPM

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Primary pulmonary artery sarcoma (PPAS) is a rare malignancy arising from mesenchymal pulmonary artery cells and mimics pulmonary embolism. Palliative chemotherapy such as anthracycline- or ifosfamide-based regimens and targeted therapy are the only options. However, the evidence of clinically beneficial systemic treatment is scarce. Here, we report a case of disseminated PPAS achieving clinical tumor response to olaparib based on comprehensive genetic profiling (CGP) showing genetic alterations involving DNA repair pathway. This provides supportive evidence that olaparib could be a promising therapeutic agent for patients with disseminated PPAS harboring actionable haploinsufficiency of DNA damage repair (DDR).

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“…DDLPS usually affects elderly patients, and the most common site is the retroperitoneum, followed by the extremities [1][2][3][4]. Genetically, DDLPS is characterized by the amplification of MDM2 and CDK4 at 12q13-15 and by ALT/WDLPS [1,2,[4][5][6]. In addition, multiple gene amplifications at 12q13-15, such as those of HMGA2, TSPAN31, and CPM, have also been identified in DDLPS [2,[4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…Genetically, DDLPS is characterized by the amplification of MDM2 and CDK4 at 12q13-15 and by ALT/WDLPS [1,2,[4][5][6]. In addition, multiple gene amplifications at 12q13-15, such as those of HMGA2, TSPAN31, and CPM, have also been identified in DDLPS [2,[4][5][6][7]. Copy number alterations (CNAs) have been reported in chromosomes other than 12q13-15, and the amplification of 1p32 and 6q23 and the loss of 11q22-24 are frequently observed [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Establishment and Characterization of NCC-DDLPS4-C1: A Novel Patient-Derived Cell Line of Dedifferentiated Liposarcoma

Tsuchiya

Yoshimatsu²,

Noguchi³

et al. 2021

JPM

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Dedifferentiated liposarcoma (DDLPS) is a highly malignant sarcoma characterized by the co-amplification of MDM2 and CDK4. Although systemic chemotherapy is recommended for unresectable or metastatic cases, DDLPS is insensitive to conventional chemotherapy, leading to an unfavorable prognosis. Therefore, novel treatment methods are urgently required. Patient-derived cell lines are essential in preclinical studies. Recently, large-scale screening studies using a number of cell lines have been actively conducted for the development of new therapeutic drugs. However, the DDLPS cell line cannot be obtained from public cell banks owing to its rarity, hindering screening studies. As such, novel DDLPS cell lines need to be established. Accordingly, this study aimed to establish a novel DDLPS cell line from surgical specimens. The cell line was named NCC-DDLPS4-C1. NCC-DDLPS4-C1 cells retained copy number alterations corresponding to the original tumors. Further, the cells demonstrated constant growth, spheroid formation, and equivalent invasiveness to MG63 osteosarcoma cells. We also conducted drug screening and integrated the results with those of the previously reported DDLPS cell lines. Consequently, we identified the histone deacetylase inhibitor romidepsin as a novel candidate drug. In conclusion, the NCC-DDLPS4-C1 cell line is a useful tool for the basic study of DDLPS.

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MDM2 Amplified Sarcomas: A Literature Review

Cited by 66 publications

References 40 publications

Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives

Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives

Transient Response of Olaparib on Pulmonary Artery Sarcoma Harboring Multiple Homologous Recombinant Repair Gene Alterations

Establishment and Characterization of NCC-DDLPS4-C1: A Novel Patient-Derived Cell Line of Dedifferentiated Liposarcoma

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