Dataset Information

Frequent HRAS Mutations in Malignant Ectomesenchymoma: Overlapping Genetic Abnormalities With Embryonal Rhabdomyosarcoma.

ABSTRACT: Malignant ectomesenchymoma (MEM) is an exceedingly rare pediatric sarcoma with a predilection for infants and young children and is composed of dual malignant mesenchymal and neuroectodermal components. Microscopically, MEM displays areas of rhabdomyosarcoma (RMS) with intermixed neuronal/neuroblastic foci. The molecular alterations associated with MEM and its relationship with embryonal RMS (ERMS) and malignant peripheral nerve sheath tumor (MPNST) have not yet been elucidated. In this study we used whole-transcriptome sequencing in 2 MEM index cases with available frozen tissue, followed by screening of the identified genetic abnormalities in 5 additional cases. No candidate fusion genes were detected by FusionSeq analysis; however, the mutation detection algorithms revealed HRAS and PTPRD hotspot mutations in both index cases, with 1 case harboring an additional FBXW7 mutation. As these mutation profiles have been previously described in ERMS we have tested their incidence in a control group of 7 age-matched ERMS. In addition, the gene signature of MEM was compared with that of RMS, MPNST, and neuronal lineage. All 7 MEM patients were male, with a mean age of 7.5 months (range, 0.6 to 17 mo). All except 1 occurred in the pelvic/urogenital region. Most cases showed ERMS elements, with occasional spindle or undifferentiated/round cell areas. The intermixed neuroectodermal components were mostly scattered ganglion cells, ganglioneuroma, or ganglioneuroblastoma. By Sanger sequencing, 6 of 7 (86%) MEMs had HRAS mutations, with no additional case harboring PTPRD or FBXW7 mutations. The only case lacking HRAS mutation showed neuroblastic micronodules without ganglion cells. The trimethylation at lysine 27 of histone H3 (H3K27me3) expression, typically lost in MPNST, was retained in all cases. In the control ERMS group, 5 of 7 (71%) showed RAS mutations, equally distributed among NRAS, KRAS, and HRAS genes. The expression profiling of MEM showed upregulation of skeletal muscle and neuronal genes, with no significant overlap with MPNST. Our results of common HRAS mutations and composite gene signature with RMS and neuronal/neuroblastic elements suggest a closer genetic link of MEM to RMS rather than to MPNST.

SUBMITTER: Huang SC

PROVIDER: S-EPMC4905780 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Frequent HRAS Mutations in Malignant Ectomesenchymoma: Overlapping Genetic Abnormalities With Embryonal Rhabdomyosarcoma.

Huang Shih-Chiang SC Alaggio Rita R Sung Yun-Shao YS Chen Chun-Liang CL Zhang Lei L Kao Yu-Chien YC Agaram Narasimhan P NP Wexler Leonard H LH Antonescu Cristina R CR

The American journal of surgical pathology 20160701 7

Malignant ectomesenchymoma (MEM) is an exceedingly rare pediatric sarcoma with a predilection for infants and young children and is composed of dual malignant mesenchymal and neuroectodermal components. Microscopically, MEM displays areas of rhabdomyosarcoma (RMS) with intermixed neuronal/neuroblastic foci. The molecular alterations associated with MEM and its relationship with embryonal RMS (ERMS) and malignant peripheral nerve sheath tumor (MPNST) have not yet been elucidated. In this study we ...[more]

PMID: 26872011

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Project description:BACKGROUND:Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). METHODS:We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. RESULTS:ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. CONCLUSION:Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

Dataset Information

Frequent HRAS Mutations in Malignant Ectomesenchymoma: Overlapping Genetic Abnormalities With Embryonal Rhabdomyosarcoma.

Publications

Frequent HRAS Mutations in Malignant Ectomesenchymoma: Overlapping Genetic Abnormalities With Embryonal Rhabdomyosarcoma.

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