Undifferentiated small round cell sarcoma in a young male: a case report

Ricker, Cora A.; Berlow, Noah; Crawford, Kenneth A.; Georgopapadakos, Todd; Huelskamp, Audrey N.; Woods, Andrew D; Dhimolea, Eugen; Ramkissoon, Shakti; Spunt, Sheri L.; Rudzinski, Erin R.; Keller, Charles

doi:10.1101/mcs.a004812

Cited by 13 publications

(13 citation statements)

References 15 publications

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“…Thus, the EEF1A1 promoter is expected to be driving transcription of the PLAG1 gene in our case 3, which was confirmed by the diffuse expression of PLAG1 in the tumor. Our case differs from other published cases that provided details of an EEF1A1 fusion 10,11 . In these cases, the fusions were not in‐frame resulting in a premature stop codon and no evidence was provided that the EEF1A1 gene fusions were indeed functional.…”

Section: Discussioncontrasting

confidence: 83%

“…In all cases, EEF1A1 was the 5′ partner, fused to HSP90AB1 in two cases of colonic adenocarcinoma, 10 PDL2 in one case of diffuse large B cell lymphoma in an 18‐year‐old male, 12 and RPL32 in a case of CIC‐DUX4 sarcoma in an 11‐year‐old male. In the last case, the fusion was only found in the post‐treatment specimen, not the initial biopsy 11 . The EEF1A1 gene encodes Eukaryotic Elongation Factor 1 Alpha 1, which is a ubiquitous protein involved in peptide elongation during mRNA translation.…”

Section: Discussionmentioning

confidence: 99%

“…Translocations involving PLAG1 have been known for some time to occur in several tumors including pleomorphic adenoma, skin and soft tissue myoepithelioma, and lipoblastoma 3‐7 . To the best of our knowledge, translocations involving YWHAZ have only been reported in two cases to date, 8,9 one of which occurred in a “fibroblastic lipoblastoma” involving PLAG1 , while translocations involving EEF1A1 have been described in four cases, 10‐12 none of which involved PLAG1 . Thus, the involvement of YWHAZ and EEF1A1 in this fibromyxoid type of pediatric tumor is unique.…”

Section: Introductionmentioning

confidence: 95%

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Pediatric fibromyxoid soft tissue tumor with PLAG1 fusion: A novel entity?

Chung

Antonescu

Dickson

et al. 2020

Genes Chromosomes & Cancer

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The classification of undifferentiated soft tissue tumors continues to evolve with the expanded application of molecular analysis in clinical practice. We report three cases of a unique soft tissue tumor in young children (5 months to 2 years old) displaying a purely fibromyxoid histology, with positive staining for desmin and CD34. In two cases, RNA sequencing detected a YWHAZ‐PLAG1 gene fusion, while in the third case, a previously unreported EEF1A1‐PLAG1 fusion was identified. PLAG1 fusions have been reported in several pathologic entities including pleomorphic adenoma, myoepithelial tumors of skin and soft tissue, and lipoblastoma, the latter occurring preferentially in young children. In these tumors, expression of a full length PLAG1 protein comes under the control of the constitutively active promoter of the partner gene in the fusion, and the current cases conform to that model. Overexpression of PLAG1 was confirmed by diffusely positive immunostaining for PLAG1 in all three cases. Our findings raise the possibility of a novel fibromyxoid neoplasm in childhood associated with these rare PLAG1 fusion variants. The only other report of a PLAG1‐YWHAZ fusion occurred in a pediatric tumor diagnosed as a “fibroblastic lipoblastoma.” This finding raises the possibility of a relationship with our three cases, even though our cases lacked any fat component. Further studies with regard to a shared pathogenesis are required.

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Section: Discussioncontrasting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Pediatric fibromyxoid soft tissue tumor with PLAG1 fusion: A novel entity?

Chung

Antonescu

Dickson

et al. 2020

Genes Chromosomes & Cancer

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“…A newly recognized commonly pediatric subtype of undifferentiated round cell sarcoma that is driven by fusion between the cell cycle regulator and transcriptional repressor, capicua (CIC), and the transcriptional activator, DUX4, has been identified based on its histology, clinical differences, and aggressiveness [1][2][3][4][5][6][7][8]. CIC-DUX4 sarcoma (CDS) occurs predominantly in children and young adults and usually develops in somatic soft tissues [4,5,9,10]. Patients with CDS show an aggressive clinical course with a high metastatic rate and quickly develop resistance to chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

Bosnakovski

Ener

Cooper³

et al. 2021

Oncogenesis

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CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.

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“…Our series adds to limited reports of molecularly targeted therapies and immunotherapeutics in CICrearranged sarcoma. 7,[13][14][15] Unfortunately, treatment efficacy was not demonstrated in our patients treated with pazopanib and pembrolizumab, with rapid disease progression occurring in both. Of patients who underwent genomic sequencing, no actionable mutations nor therapeutic options were identified.…”

Section: Systemic Treatmentsmentioning

confidence: 81%

Systemic treatments and outcomes in CIC‐rearranged Sarcoma: A national multi‐centre clinicopathological series and literature review

et al. 2022

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CIC ‐rearranged sarcoma is a recently established, ultra‐rare, molecularly defined sarcoma subtype. We aimed to further characterise clinical features of CIC ‐rearranged sarcomas and explore clinical management including systemic treatments and outcomes. Methods A multi‐centre retrospective cohort study of patients diagnosed between 2014–2019. Results Eighteen patients were identified. The median age was 27 years (range 13–56), 10 patients were male (56%), 11 patients (61%) had localised disease and 7 patients had advanced (metastatic or unresectable) disease at diagnosis. Of 11 patients with localised disease at diagnosis, median overall survival (OS) was 40.6 months and the 1‐, 2‐ and 5‐year OS estimates were 82%, 64% and 34% respectively. Nine patients (82%) underwent surgery (all had R0 resections), 8 (73%) patients received radiotherapy to the primary site (median dose 57Gy in 28 fractions), and 8 (73%) patients received chemotherapy (predominantly Ewing‐based regimens). Metastases developed in 55% with a median time to recurrence of 10.5 months. In patients with advanced disease at diagnosis, median OS was 12.6 months (95% CI 5.1–20.1), 1‐year OS was 57%. Median progression‐free survival was 5.8 months (95% CI 4.5–7.2). Durable systemic therapy responses occurred infrequently with a median duration of systemic treatment response of 2.1 months. One durable complete response of metastatic disease to VDC/IE chemotherapy was seen. Responses to pazopanib ( n = 1) and pembrolizumab ( n = 1) were not seen. Conclusion In this series, CIC ‐rearranged sarcomas affected young adults and had a high incidence of presenting with, or developing, metastatic disease. The prognosis overall was poor. In advanced disease, durable systemic therapy responses were infrequent.

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Undifferentiated small round cell sarcoma in a young male: a case report

Cited by 13 publications

References 15 publications

Pediatric fibromyxoid soft tissue tumor with PLAG1 fusion: A novel entity?

Pediatric fibromyxoid soft tissue tumor with PLAG1 fusion: A novel entity?

Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

Systemic treatments and outcomes in CIC‐rearranged Sarcoma: A national multi‐centre clinicopathological series and literature review

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