DUX4 Immunohistochemistry Is a Highly Sensitive and Specific Marker for CIC-DUX4 Fusion-positive Round Cell Tumor

Siegele, Bradford; Roberts, Jon; Black, Jennifer O.; Rudzinski, Erin R.; Vargas, Sara O.; Galambos, Csaba

doi:10.1097/pas.0000000000000772

Cited by 62 publications

(39 citation statements)

References 19 publications

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“…Ewing sarcoma, alveolar rhabdomyosarcoma, synovial sarcoma, desmoplastic small round cell tumor) did not. 27 DUX4 gene is located within the D4Z4 macrosatellite repeat region (11–100 copies of the repeat units) of the chromosomes 4 and 10 subtelomeric regions. 28 …”

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

307

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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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

307

338

View full text Add to dashboard Cite

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“…CIC alterations have also been reported in “Ewing‐like tumors,” with the most common fusion partner being DUX4 . These tumors are characterized by a predominately small round blue cell morphology, often with focal cell spindling, nuclear atypia, and stromal changes …”

Section: Novel and Rare Fusion Events In Pediatric Gliomasmentioning

confidence: 99%

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

Lake

Donson

Prince

et al. 2019

Pediatric Blood & Cancer

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Background The use of next‐generation sequencing for fusion identification is being increasingly applied and aids our understanding of tumor biology. Some fusions are responsive to approved targeted agents, while others have future potential for therapeutic targeting. Although some pediatric central nervous system tumors may be cured with surgery alone, many require adjuvant therapy associated with acute and long‐term toxicities. Identification of targetable fusions can shift the treatment paradigm toward earlier integration of molecularly targeted agents. Methods Patients diagnosed with glial, glioneuronal, and ependymal tumors between 2002 and 2019 were retrospectively reviewed for fusion testing. Testing was done primarily using the ArcherDx FusionPlex Solid Tumor panel, which assesses fusions in 53 genes. In contrast to many previously published series chronicling fusions in pediatric patients, we compared histological features and the tumor classification subtype with the specific fusion identified. Results We report 24 cases of glial, glioneuronal, or ependymal tumors from pediatric patients with identified fusions. With the exception of BRAF:KIAA1549 and pilocytic/pilomyxoid astrocytoma morphology, and possibly QKI‐MYB and angiocentric glioma, there was not a strong correlation between histological features/tumor subtype and the specific fusion. We report the unusual fusions of PPP1CB‐ALK, CIC‐LEUTX, FGFR2‐KIAA159, and MN1‐CXXC5 and detail their morphological features. Conclusions Fusion testing proved to be informative in a high percentage of cases. A large majority of fusion events in pediatric glial, glioneuronal, and ependymal tumors can be identified by relatively small gene panels.

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“…Morphologically, CIC‐DUX4 sarcoma shows more varied cytomorphology, often with areas of epithelioid or spindled cells. A monoclonal antibody directed against a conserved region present in both DUX4 homologs (encoded on either 4q35 or 10q26) has recently been investigated in a small series . The authors demonstrated diffuse nuclear staining in all cases, whereas all other round cell tumors were negative.…”

Section: Gene Fusionsmentioning

confidence: 99%

Immunohistochemical correlates of recurrent genetic alterations in sarcomas

Anderson

Hornick

2018

Genes Chromosomes & Cancer

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Accurate diagnosis of sarcomas relies on the integration of clinical, histopathological and molecular features. Our understanding of the latter has increased dramatically in recent years with the application of high‐throughput sequencing. Concomitantly, the role of immunohistochemistry has expanded as genomic alterations have been exploited by the development of diagnostic markers that serve as surrogates for their detection. Herein, we review selected immunohistochemical markers that can infer the presence of diverse molecular events. These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan‐TRK); amplifications in well‐differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4). Protein correlates of single nucleotide variants (beta‐catenin in desmoid fibromatosis) and epigenetic alterations (histone H3K27me3 in malignant peripheral nerve sheath tumor) and markers discovered through gene expression profiling (NKX2.2 and MUC4) are also discussed.

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DUX4 Immunohistochemistry Is a Highly Sensitive and Specific Marker for CIC-DUX4 Fusion-positive Round Cell Tumor

Cited by 62 publications

References 19 publications

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

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

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

Immunohistochemical correlates of recurrent genetic alterations in sarcomas

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