Extraskeletal myxoid chondrosarcoma with a t(9;16)(q22;p11.2) resulting in a NR4A3-FUS fusion

Broehm, Cory; Wu, Jin; Gullapalli, Rama R.; Bocklage, Thèrése

doi:10.1016/j.cancergen.2014.06.024

Cited by 32 publications

(26 citation statements)

References 23 publications

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“…TCF12 was conspicuously downregulated in the vast majority of OSCC tumors. As TCF12 has many spliced variants and it is prone to get mutated or translocated in diseases (29,30), to further define its functional implications and to characterize the genomic abnormalities in a wide variety of malignancies is required. Antibodies detecting nuclear TCF12 activity more specifically are required to facilitate tissue studies.…”

Section: Association Between Fam213a Expression and Poor Patient Survmentioning

confidence: 99%

“…TCF12 was shown to regulate the differentiation of lymphocytes or the development of neural or mesenchymal tissues (25)(26)(27)(28). Recurrent mutations in TCF12 gene or the translocation fusion of a fragment of TCF12 with other molecules contribute to craniosynostosis or mesenchymal malignancies (29,30). In colorectal cancer, TCF12 expression correlated with metastasis by repression of E-cadherin (22).…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

Chen¹,

et al. 2016

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miR-211 expression in human oral squamous cell carcinoma (OSCC) has been implicated in poor patient survival. To investigate the oncogenic roles of miR-211, we generated K14-EGFPmiR-211 transgenic mice tagged with GFP. Induction of oral carcinogenesis in transgenic mice using 4-nitroquinoline 1-oxide (4NQO) resulted in more extensive and severe tongue tumorigenesis compared with control animals. We found that 4NQO and arecoline upregulated miR-211 expression in OSCC cells. In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically downregulated in tumor tissues. We used GeneChip analysis and bioinformatic algorithms to identify transcriptional targets of TCF12 and confirmed through reporter and ChIP assays that family with sequence similarity 213, member A (FAM213A), a peroxiredoxin-like antioxidative protein, was repressed transcriptionally by TCF12. FAM213A silencing in OSCC cells diminished oncogenic activity, reduced the ALDH1-positive cell population, and increased reactive oxygen species. TCF12 and FAM213A expression was correlated inversely in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients bearing tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment downregulated TCF12 and upregulated FAM213A by modulating miR-211 both in vitro and in vivo. Overall, our findings develop a mouse model that recapitulates the molecular and histopathologic alterations of human OSCC pathogenesis and highlight a new miRNA-mediated oncogenic mechanism. Cancer Res; 76(16); 4872-86. Ó2016 AACR.

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Section: Association Between Fam213a Expression and Poor Patient Survmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

Chen¹,

et al. 2016

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“…In about 75% of cases a t(9;22)(q22; q12) is found, which results in the fusion of the EWSR1 gene on chromosome 22 with NR4A3 on chromosome 9 . Other alternative partners for NR4A3 have been described, resulting in gene fusions occurring between NR4A3 and TAF15 , TCF12 , TGF and FUS in a subset of tumors . Very recently, a novel gene partner for NR4A3 have been reported involving the HSPA8 gene by whole‐transcriptome sequencing, further expanding the list of NR4A3 fusion partners in EMC …”

Section: Introductionmentioning

confidence: 99%

“…[10][11][12] Other alternative partners for NR4A3 have been described, resulting in gene fusions occurring between NR4A3 and TAF15, TCF12, TGF and FUS in a subset of tumors. 12,14 Very recently, a novel gene partner for NR4A3 have been reported involving the HSPA8 gene by wholetranscriptome sequencing, further expanding the list of NR4A3 fusion partners in EMC. 13 Since its first description in 1984 by Calafati,15 few reports on the cytological features of EMC have been published and most of the literature is based on single-case reports and small series.…”

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confidence: 99%

Fine‐needle aspiration features of extraskeletal myxoid chondrosarcoma: A study of cytological and molecular features

Santos¹,

Martins

Lemos³

2018

Diagnostic Cytopathology

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Background Extraskeletal myxoid chondrosarcoma (EMC) is a tumor of uncertain differentiation. Few data are available regarding its cytomorphological features in fine‐needle aspiration (FNA). Specific cytogenetic alterations involving the NR4A3 gene are found in EMC and can be identified in FNA samples. Methods We retrospectively reviewed 14 FNAs performed in 11 patients with an EMC; 10 FNAs were performed preoperatively on primary tumors; 2 were performed on recurrences and 2 were performed on metastasis. Cytological features were compared with histological findings. Immunohistochemistry (IHC) and molecular studies were performed both in FNA and histological specimens. Results A preoperative cytological diagnosis of EMC was rendered in eight FNAs performed in newly diagnosed tumors and in recurrent/metastatic cases. A descriptive diagnosis of a myxoid neoplasm was made in the remaining two cases. Smears were moderately hypercellular, composed of plasmocytoid to fusiform cells, with scant, pale cytoplasm, bland nuclei and inconspicuous nucleoli, dispersed as cords, strands and occasionally with a lace‐like pattern, in an abundant chondromyxoid matrix. IHC performed showed focal positivity for S100 and NSE. Fluorescence in situ hybridization technique performed in three FNA specimens showed EWSR1 gene rearrangements in all, concomitant with NR4A3 gene rearrangement in one case. Histological specimens showed typical features of EMC and NR4A3 gene rearrangements were found in all cases tested. Conclusion FNA cytology is a reliable method to perform a preoperative diagnosis of EMC regarding its cytomorphological and molecular features. Main differential diagnoses include myoepithelial tumors of soft tissue, myxoid liposarcoma and myxofibrosarcoma. Ancillary studies are helpful when coupled with cytomorphology evaluation.

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“…3,4 Extraskeletal myxoid chondrosarcoma harbors specific recurrent chromosomal translocations in over 95% of cases, which create fusions involving the whole coding sequence of NR4A3 (NOR1, CHN, or TEC, located at 9q22). The most frequent fusion partner of NR4A3 is EWSR1 (22q12, 60-75%), 5 followed by TAF15 (RBP56 or TAF2N; 17q11, 15-20%), and other rare targets, such as TCF12 (15q21), TFG (3q12), 6 FUS (16p11), 7 and HSPA8 (11q24.1), 8 each accounting for o 3%. 9 Surgical resection is the primary therapy and the tumor follows a relatively protracted clinical course with a propensity for late recurrence and distant metastases.…”

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confidence: 99%

INSM1 expression and its diagnostic significance in extraskeletal myxoid chondrosarcoma

et al. 2018

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Extraskeletal myxoid chondrosarcoma is a rare subtype of sarcoma that affects the soft tissue and bones in middle-aged and elderly adults. Its diagnosis can be challenging, with the differential diagnoses including a wide variety of mesenchymal tumors. The line of differentiation of extraskeletal myxoid chondrosarcoma has been controversial, but recent evidence suggests a neuroendocrine phenotype. INSM1 is a zinc-finger transcription factor that plays a pivotal role in neuroendocrine differentiation, and has been proposed as a promising immunohistochemical marker of neuroendocrine carcinoma. The aim of this study was to determine the prevalence of INSM1 expression in extraskeletal myxoid chondrosarcoma and to understand its significance in sarcoma diagnosis. We immunostained the representative sections of 31 NR4A3-rearranged extraskeletal myxoid chondrosarcomas and 187 histological mimics. Nuclear staining of moderate or higher intensity in at least 5% of tumor cells was considered positive. Twenty-eight of the 31 extraskeletal myxoid chondrosarcomas (90%) were positive for INSM1, providing strong evidence for neuroendocrine differentiation. The staining was diffuse (>50%) in 17 cases, with most immunopositive tumors showing at least focal strong expression. The INSM1 staining extent was not correlated with cytomorphology, synaptophysin expression, or fusion types (EWSR1 vs non-EWSR1). In contrast, INSM1 expression was negative in 94% of the 187 other mesenchymal tumors. INSM1-positive mimics comprised a small subset of chordoma (1 of 10), soft tissue myoepithelioma (1 of 20), ossifying fibromyxoid tumor (3 of 10), and Ewing sarcoma (3 of 10), among other tumor types. The majority of these cases showed labeling in <25% of the tumor cells. Although not entirely sensitive or specific, INSM1 could be a potential marker for the diagnosis of extraskeletal myxoid chondrosarcoma when molecular genetic access is limited.

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Extraskeletal myxoid chondrosarcoma with a t(9;16)(q22;p11.2) resulting in a NR4A3-FUS fusion

Cited by 32 publications

References 23 publications

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

Fine‐needle aspiration features of extraskeletal myxoid chondrosarcoma: A study of cytological and molecular features

INSM1 expression and its diagnostic significance in extraskeletal myxoid chondrosarcoma

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