Dataset Information

EWSR1-NFATC2 and FUS-NFATC2 Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review.

ABSTRACT: The spectrum of mesenchymal tumors associated with rearrangements of the EWSR1 gene has been growing in recent years due to progress in molecular detection techniques. Originally identified as the gene involved in the pathogenesis of Ewing sarcoma, the EWSR1 gene is now known to be rearranged in diverse clinical and histopathological entities. The NFATC2 gene is one of the many translocation partners of EWSR1 in gene fusions in a morphologically typical, albeit rare, subgroup of mesenchymal tumors. Little is known about the clinical characteristics of tumors containing NFATC2 gene rearrangements since most of the few reports published describe molecular rather than clinical aspects. In the current study, we report three patients with tumors carrying the EWSR1-NFATC2 gene translocation, including one rare primary tumor of soft tissues. Another patient with a benign-appearing bone tumor with a unique FUS-NFATC2 gene translocation is described. In various mesenchymal tumors (e.g., myxoid/round cell liposarcoma, low-grade fibromyxoid sarcoma, or angiomatoid fibrous histiocytoma), the FUS gene, as a member of the TET family, may be alternatively rearranged instead of the EWSR1 gene without any noticeable influence on the microscopical appearance or clinical outcome. This fact seems not to apply to mesenchymal tumors with the involvement of the NFATC2 gene because both in our experience and according to the extensive literature review, they have different properties on the morphological and molecular level. Both ESWSR1-NFATC2 and FUS-NFATC2 fusion-carrying tumors do not show microscopical or clinical features of Ewing sarcoma.

SUBMITTER: Bode-Lesniewska B

PROVIDER: S-EPMC6458862 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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EWSR1-NFATC2 and FUS-NFATC2 Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review.

Bode-Lesniewska Beata B Fritz Christine C Exner Gerhard Ulrich GU Wagner Ulrich U Fuchs Bruno B

Sarcoma 20190326

The spectrum of mesenchymal tumors associated with rearrangements of the EWSR1 gene has been growing in recent years due to progress in molecular detection techniques. Originally identified as the gene involved in the pathogenesis of Ewing sarcoma, the EWSR1 gene is now known to be rearranged in diverse clinical and histopathological entities. The NFATC2 gene is one of the many translocation partners of EWSR1 in gene fusions in a morphologically typical, albeit rare, ...[more]

PMID: 31049020

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Project description:Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4 years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33 months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.

Project description:To elucidate the mechanisms underlying the divergent clinicopathologic spectrum of EWSR1/FUS::CREB translocation-associated tumors, we performed a comprehensive genomic analysis of fusion transcript variants, recurrent genetic alterations (mutations, copy number alterations), gene expression, and methylation profiles across a large cohort of tumor types. The distribution of the EWSR1/FUS fusion partners-ATF1, CREB1, and CREM-and exon involvement was significantly different across different tumor types. Our targeted sequencing showed that secondary genetic events are associated with tumor type rather than fusion type. Of the 39 cases that underwent targeted NGS testing, 18 (46%) had secondary OncoKB mutations or copy number alterations (29 secondary genetic events in total), of which 15 (52%) were recurrent. Secondary recurrent, but mutually exclusive, TERT promoter and CDKN2A mutations were identified only in clear cell sarcoma (CCS) and associated with worse overall survival. CDKN2A/B homozygous deletions were recurrent in angiomatoid fibrous histiocytoma (AFH) and restricted to metastatic cases. mRNA upregulation of MITF, CDH19, PARVB, and PFKP was found in CCS, compared to AFH, and correlated with a hypomethylated profile. In contrast, S100A4 and XAF1 were differentially upregulated and hypomethylated in AFH but not CCS. Unsupervised clustering of methylation profiles revealed that CREB family translocation-associated tumors form neighboring but tight, distinct clusters. A sarcoma methylation classifier was able to accurately match 100% of CCS cases to the correct methylation class; however, it was suboptimal when applied to other histologies. In conclusion, our comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovered mostly histotype, rather than fusion-type associated correlations in transcript variants, prognostically significant secondary genetic alterations, and gene expression and methylation patterns.

Dataset Information

EWSR1-NFATC2 and FUS-NFATC2 Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review.

Publications

<i>EWSR1-NFATC2</i> and <i>FUS-NFATC2</i> Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review.

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