<i><scp>CIC</scp>–<scp>DUX</scp>4</i> fusion‐positive round‐cell sarcomas of soft tissue and bone: a single‐institution morphological and molecular analysis of seven cases

Gambarotti, Marco; Benini, Stefania; Gamberi, Gabriella; Cocchi, Stefania; Palmerini, Emanuela; Sbaraglia, Marta; Donati, Davide María; Picci, Piero; Vanel, D.; Ferrari, Stefano; Righi, Alberto; Tos, Angelo Paolo Dei

doi:10.1111/his.12985

Cited by 80 publications

(70 citation statements)

References 28 publications

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“…In CDS, the abundant ECM noted correlated with an upregulation of various collagen genes, their modifying enzymes and matrix proteases, consistent with enhanced ECM induction (28). Similarly, abundant ECM in CDS was also reported in human CDS either as dense fibrous septa or myxoid stroma (29). Interestingly, spontaneous hematogenous metastases, which were never found in the ES mouse model, were observed in the CDS model, which might be related to enhanced vasculogenesis in CDS.…”

Section: Discussionmentioning

confidence: 61%

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

et al. 2017

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CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Hoever, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA. Recipient mice transplanted with eMC expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small-round to short-spindle cells. Gene expression profiles of CDS and eMC revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh and Zic1. Immunohistochemical analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro. The CDK4/6 inhibitor palbociclib and the soft tissue sarcoma drug trabectedin also blocked the growth of mouse CDS. In summary, our mouse model provides important biological information about CDS and provides a useful platform to explore biomarkers and therapeutic agents for CDS.

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Section: Discussionmentioning

confidence: 61%

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

et al. 2017

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“…Stromal myxoid change was a common finding in CIC -positive tumors, which is typically absent in Ewing sarcoma. 13,14 …”

Section: Discussionmentioning

confidence: 99%

Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome

Antonescu¹,

Owosho²,

Zhang³

et al. 2017

American Journal of Surgical Pathology

320

338

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CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors (SBRCTs). Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (i.e. atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, in order to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared to a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, while nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (p=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared to Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of SBRCTs distinct from Ewing sarcoma.

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“…Several approaches are possible. FISH is a well-established method, and break-apart probes for CIC are commercially available 13 14. The break-apart FISH assay will identify cases with CIC translocation regardless of the gene partner, and in this context, it should be noted that rare cases of Ewing-like sarcomas with a variant CIC-FOXO4 gene fusion have been reported,15 16 and will not be distinguished from CIC-DUX4 cases by this approach.…”

Section: Discussionmentioning

confidence: 99%

Novel exon–exon breakpoint inCIC-DUX4fusion sarcoma identified by anchored multiplex PCR (Archer FusionPlex Sarcoma Panel)

et al. 2017

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CIC–DUX4 fusion‐positive round‐cell sarcomas of soft tissue and bone: a single‐institution morphological and molecular analysis of seven cases

Abstract: Our series confirms that CIC-DUX4 fusion-positive sarcomas are aggressive tumours with an adverse prognosis, and with clinical, histological and genetic differences from Ewing sarcoma. The best therapeutic approach needs to be investigated.

Cited by 80 publications

References 28 publications

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome

Novel exon–exon breakpoint inCIC-DUX4fusion sarcoma identified by anchored multiplex PCR (Archer FusionPlex Sarcoma Panel)

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