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Zhan X, Liu Y, Jannu AJ, Huang S, Ye B, Wei W, Pandya PH, Ye X, Pollok KE, Renbarger JL, Huang K, Zhang J. Identify potential driver genes for PAX-FOXO1 fusion-negative rhabdomyosarcoma through frequent gene co-expression network mining. Front Oncol 2023; 13:1080989. [PMID: 36793601 PMCID: PMC9924292 DOI: 10.3389/fonc.2023.1080989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/12/2023] [Indexed: 02/03/2023] Open
Abstract
Background Rhabdomyosarcoma (RMS) is a soft tissue sarcoma usually originated from skeletal muscle. Currently, RMS classification based on PAX-FOXO1 fusion is widely adopted. However, compared to relatively clear understanding of the tumorigenesis in the fusion-positive RMS, little is known for that in fusion-negative RMS (FN-RMS). Methods We explored the molecular mechanisms and the driver genes of FN-RMS through frequent gene co-expression network mining (fGCN), differential copy number (CN) and differential expression analyses on multiple RMS transcriptomic datasets. Results We obtained 50 fGCN modules, among which five are differentially expressed between different fusion status. A closer look showed 23% of Module 2 genes are concentrated on several cytobands of chromosome 8. Upstream regulators such as MYC, YAP1, TWIST1 were identified for the fGCN modules. Using in a separate dataset we confirmed that, comparing to FP-RMS, 59 Module 2 genes show consistent CN amplification and mRNA overexpression, among which 28 are on the identified chr8 cytobands. Such CN amplification and nearby MYC (also resides on one of the above cytobands) and other upstream regulators (YAP1, TWIST1) may work together to drive FN-RMS tumorigenesis and progression. Up to 43.1% downstream targets of Yap1 and 45.8% of the targets of Myc are differentially expressed in FN-RMS vs. normal comparisons, which also confirmed the driving force of these regulators. Discussion We discovered that copy number amplification of specific cytobands on chr8 and the upstream regulators MYC, YAP1 and TWIST1 work together to affect the downstream gene co-expression and promote FN-RMS tumorigenesis and progression. Our findings provide new insights for FN-RMS tumorigenesis and offer promising targets for precision therapy. Experimental investigation about the functions of identified potential drivers in FN-RMS are in progress.
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Affiliation(s)
- Xiaohui Zhan
- Department of Bioinformatics, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Yusong Liu
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China
| | - Asha Jacob Jannu
- Department of Biostatistics and Health Data Science, Indiana University, School of Medicine, Indianapolis, IN, United States
| | | | - Bo Ye
- Department of Bioinformatics, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Wei Wei
- Department of Bioinformatics, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Pankita H Pandya
- Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, IN, United States
| | - Xiufen Ye
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China
| | - Karen E Pollok
- Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, IN, United States
| | - Jamie L Renbarger
- Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, IN, United States
| | - Kun Huang
- Department of Biostatistics and Health Data Science, Indiana University, School of Medicine, Indianapolis, IN, United States
| | - Jie Zhang
- Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN, United States
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Panferova A, Sinichenkova KY, Abu Jabal M, Usman N, Sharlai A, Roshchin V, Konovalov D, Druy A. EWSR1-TFCP2 in an adolescent represents an extremely rare and aggressive form of intraosseous spindle cell rhabdomyosarcomas. Cold Spring Harb Mol Case Stud 2022; 8:mcs.a006209. [PMID: 35768243 PMCID: PMC9528966 DOI: 10.1101/mcs.a006209] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/09/2022] [Indexed: 10/30/2022] Open
Abstract
The WHO Classification of Tumors of Soft Tissue and Bone subdivides rhabdomyosarcomas (RMS) into alveolar, embryonal, pleomorphic, and spindle cell RMS. Advances in molecular genetic diagnostics have made it possible to identify new RMS subgroups within traditional morphological entities. One of these subgroups comprises rare tumors characterized by epithelioid and spindle cell morphology, highly aggressive clinical course with pronounced tendency to intraosseous growth, and the presence of pathognomonic recurring genetic aberrations- chimeric genes/transcripts EWSR1::TFCP2, FUS::TFCP2, or MEIS1::NCOA2. Starting from 2018, only 26 reported cases of RMS have been assigned to this subgroup. The rarity of such tumors hampers their correct diagnostics for both anatomic pathologists and molecular oncologists. Here we describe a clinical case of intraosseous spindle cell RMS expressing EWSR1::TFCP2 fusion gene, encountered for the first time in our practice, in a 16-year-old female patient presenting with mandibular lesion. The diagnostic process took considerable time and involved RNA sequencing; a high-throughput method of molecular genetic research. The tumor was extremely aggressive, showing resistance to polychemotherapy, radiation therapy, and crizotinib targeted therapy, with the fatal outcome.
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Affiliation(s)
- Agnesa Panferova
- Dmitry Rogachev National Medical Research Center Of Pediatric Hematology, Oncology and Immunology;
| | - Kseniya Yu Sinichenkova
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Meriam Abu Jabal
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Natalia Usman
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Anastasya Sharlai
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Vitalii Roshchin
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Dmitry Konovalov
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Alexander Druy
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
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Satală CB, Jung I, Bara TJ, Simu P, Simu I, Vlad M, Szodorai R, Gurzu S. Primary rhabdomyosarcoma: An extremely rare and aggressive variant of male breast cancer. World J Clin Cases 2020; 8:4466-4474. [PMID: 33083405 PMCID: PMC7559662 DOI: 10.12998/wjcc.v8.i19.4466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 07/28/2020] [Accepted: 09/04/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Rhabdomyosarcoma (RMS) of the breast, a mesenchymal neoplasm with skeletal muscle differentiation, is an extremely rare tumour in males, with less than 30 cases published in English-language literature. We report on the first case of a male breast RMS, with an unusual ectomesenchymal/neuroectodermal component. CASE SUMMARY A 55-year-old, previously healthy male, underwent a radical left mastectomy for an ulcerated tumour mass, occupying the breast and left anterior thoracic wall. The biopsy specimen indicated the presence of a tumour with neural origins, namely a peripheral neuroectodermal tumour (PNET). The surgical specimens identified two components. The rhabdomyosarcomatous component (over 70%) was represented by large pleomorphic cells with positivity for desmin, sarcomeric actin and myogenin. The PNET-like ectomesenchymal component, which was admixed with the RMS cells, and was also revealed during the preoperative biopsy, consisted of small cells which expressed neurofilament, neuron specific enolase and CD99. The microscopic examination, along with the immunohistochemical profile, allowed the diagnosis of an RMS, with unusual ectomesenchymal differentiation. The patient refused the postoperative oncologic therapy and died three months after surgery. CONCLUSION In patients with RMS of the breast, the PNET-like ectomesenchymal component increases the diagnosis difficulty, especially in biopsy specimens. This differentiation can be immunohistochemically proven and might highlight the possible development of high-grade sarcoma of the breast from remnants of the embryological ectodermal layer.
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Affiliation(s)
- Cătălin Bogdan Satală
- Department of Pathology, Clinical County Emergency Hospital, Tirgu Mures 540139, Romania
| | - Ioan Jung
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 530149, Romania
| | - Tivadar Jr Bara
- Department of Surgery, Clinical County Emergency Hospital, Targu Mures 540136, Romania
| | - Patricia Simu
- Department of Radiology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 530149, Romania
| | - Iunius Simu
- Department of Radiology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 530149, Romania
| | - Madalina Vlad
- Department of Pathology, Clinical County Emergency Hospital, Targu Mures 540136, Romania
| | - Rita Szodorai
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 530149, Romania
| | - Simona Gurzu
- Department of Pathology, Clinical County Emergency Hospital, Targu Mures 540136, Romania
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, Targu Mures 530149, Romania
- Research Center (CCAMF), University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 540139, Romania
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Kilic-Kurt Z, Bakar-Ates F, Bahat M. N,N′-diaryl urea derivatives: Molecular docking, molecular properties prediction and anticancer evaluation. J Mol Struct 2019. [DOI: 10.1016/j.molstruc.2019.05.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells. Cell Death Discov 2018; 4:52. [PMID: 30416757 PMCID: PMC6202374 DOI: 10.1038/s41420-018-0115-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 09/20/2018] [Accepted: 09/26/2018] [Indexed: 02/08/2023] Open
Abstract
Rhabdomyosarcoma (RMS) is a muscle-derived tumor. In both pre-clinical and clinical studies Temozolomide (TMZ) has been recently tested against RMS; however, the precise mechanism of action of TMZ in RMS remains unclear. Here we demonstrate that TMZ decreases the cell viability of the RH30 RMS and C2C12 cell line, where cells display evidence of mitochondrial outer membrane permeability. Interestingly, the C2C12 mouse myoblast line was relatively more resistant to TMZ-induced apoptosis. Moreover, we observed that TMZ activated biochemical and morphological markers of autophagy in both cell lines. Autophagy inhibition in both RH30 and C2C12 cells significantly increased TMZ-induced cell death. In RH30 cells, TMZ increased Mcl-1 and Bax protein expression compared to corresponding time match controls while in C2C12 Mcl-1, Bcl-2, Bcl-XL, and Bax protein expression were not changed. Baf-A1 co-treatment with TMZ significantly decrease Mcl-1 expression compared to TMZ while increase Bax expression in C2C12 cells (Bcl2 and Bcl-XL do not significantly change in Baf-A1/TMZ co-treatment). Using a three-dimensional (3D) C2C12 and RH30 culture model we demonstrated that TMZ is significantly more toxic in RH30 cells (live/dead assay). Additionally, we have observed in our 3D culture model that TMZ induced both apoptosis (cleavage of PARP) and autophagy (LC3-puncta and localization of LC3/p62). Therefore, our data demonstrate that TMZ induces simultaneous autophagy and apoptosis in both RH30 and C2C12 cells in 2D and 3D culture model, where RH30 cells are more sensitive to TMZ-induced death. Furthermore, autophagy serves to protect RH30 cells from TMZ-induced death.
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