Gene Summary

Gene:FUS; FUS RNA binding protein
Aliases: TLS, ALS6, ETM4, FUS1, POMP75, HNRNPP2
Summary:This gene encodes a multifunctional protein component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. The hnRNP complex is involved in pre-mRNA splicing and the export of fully processed mRNA to the cytoplasm. This protein belongs to the FET family of RNA-binding proteins which have been implicated in cellular processes that include regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. Alternative splicing results in multiple transcript variants. Defects in this gene result in amyotrophic lateral sclerosis type 6. [provided by RefSeq, Sep 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:RNA-binding protein FUS
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FUS (cancer-related)

Sambri A, Righi A, Tuzzato G, et al.
Low-grade fibromyxoid sarcoma of the extremities: a clinicopathologic study of 24 cases and review of the literature.
Pol J Pathol. 2018; 69(3):219-225 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) and hybrid sclerosing epithelioid fibrosarcoma (SEF)/LGFMS have a low potential for recurrence (10%) and metastasis (5%) but they are notorious for late occurring metastases. The aim of this study was to evaluate the outcome of LGFMS and review similar cases reported in the literature. We retrospectively evaluated 24 LGFMS operated at a single Institution. All cases were histologically revised. Mean age was 34 years (range, 8 to 74). Two cases presented areas of SEF (hybrid tumours). Three patients presented with metastasis at diagnosis. A strong cytoplasmic staining for MUC4 antibody was found in the majority of neoplastic cells. RT-PCR was feasible in 6 cases and it detected the presence of FUS-CREB3L2 fusion gene chimeric transcript. Mean follow-up was 44 months (range, 6 to 217). Two patients developed lung metastasis after 9 and 26 months respectively. Low-grade fibromyxoid sarcoma has a various histopathologic spectrum with few cases of LGFMS that share histopathologic resemblance with SEF, thereby reinforcing a possibility of a link within these two. It is of paramount importance an accurate and extensive sampling and examination of the whole specimen, in order to identify higher risk patients.

Zerkalenkova E, Panfyorova A, Kazakova A, et al.
Molecular characteristic of acute leukemias with t(16;21)/FUS-ERG.
Ann Hematol. 2018; 97(6):977-988 [PubMed] Related Publications
T(16;21)(p11;q22)/FUS-ERG is a rare but recurrent translocation in acute leukemias and in some types of solid tumors. Due to multiple types of FUS-ERG transcripts, PCR-based minimal residual disease detection is impeded. In this study, we evaluated a cohort of pediatric patients with t(16;21)(p11;q22)/FUS-ERG and revealed fusion gene breakpoints. We implemented next-generation sequencing (NGS) on long PCR amplicons for the detection of fusion genes with unknown partners or DNA breakpoints. That allowed us to describe different fusion variants of FUS/ERG in different patients and to detect MRD on both RNA and DNA levels. We also found several accompanying mutations in epigenetic regulators (DNMT3A, ASXL1, BCOR) by targeted NGS approach in AML cases. These mutations preceded full transformation by t(16;21)(p11;q22)/FUS-ERG and allowed us to trace clonal evolution on all steps of therapy. As a casual observation, the ASXL1 mutation was found in the unrelated donor hematopoietic cells.

Tang X, Zhou J, Zhang J, et al.
Low Expression of FUS1 Is Negatively Correlated with miR-378 and May Predict Adverse Prognoses in Acute Myeloid Leukemia.
Acta Haematol. 2018; 139(2):89-95 [PubMed] Related Publications
FUS1 is a tumor suppressor gene that has been found to be frequently lost in a variety of solid tumors. In this study, we aimed to investigate the expression status of the FUS1 gene in acute myeloid leukemia (AML), as well as its clinical significance. We further explored the correlation between the expression of FUS1 and miR-378 in AML. We detected expression of the FUS1 transcript in bone marrow mononuclear cells from 23 controls and 158 newly diagnosed AML patients by real-time quantitative polymerase chain reaction. Downregulated FUS1 expression was found in 139 out of 158 (87.97%) AML cases; this rate was significantly lower than that in all 23 controls (p = 0.012). Receiver operating characteristic curve analysis revealed that the FUS1 transcript level could discriminate AML patients from controls effectively (area under the ROC curve = 0.663). Kaplan-Meier analysis demonstrated that non-M3-AML patients with a low FUS1 expression had a shorter overall survival (p = 0.049) and leukemia-free survival (p = 0.051) than those with a high FUS1 expression. Furthermore, we studied the correlation between the expression of FUS1 and miR-378 in 53 newly diagnosed AML patients. We found that the correlation coefficient was -0.346, which showed that FUS1 and miR-378 were negatively correlated in AML patients (p = 0.011). These results indicate that the low expression of FUS1 is a common molecular event in AML.

Qin YZ, Chen Y, Xu LP, et al.
Outcome and Minimal Residual Disease Monitoring in Patients with t(16;21) Acute Myelogenous Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.
Biol Blood Marrow Transplant. 2018; 24(1):163-168 [PubMed] Related Publications
Patients with t(16;21) acute myelogenous leukemia (AML) who receive chemotherapy have poor outcomes. The treatment efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) must be identified, and the usefulness of minimal residual disease (MRD) monitoring requires evaluation. Fourteen consecutive patients with t(16;21) AML undergoing allo-HSCT at our institution were included in this study. Translocation liposarcoma- ETS-related gene (TLS-ERG) transcript levels were serially monitored for a median of 15 months (range, 3-51 months) after allo-HSCT. Eight patients relapsed, 7 patients died from relapse-related causes, and 1 patient died from a non-relapse-related cause. The 2-year cumulative incidence rates of relapse, disease-free survival, and overall survival after HSCT were 66.2%, 30.8%, and 46.2%, respectively. Of the 3 patients who received an HLA-matched sibling transplant, 2 relapsed, and 1 (33.3%) was in hematologic complete remission (CR) but died of nonrelapse mortality, whereas 5 of 11 patients (45.5%) who received haploidentical transplantation were in CR and were alive. Two of 6 patients with undetectable TLS-ERG at the time of allo-HSCT relapsed, at 14 and 15 months, and 3 of 4 PCR-positive patients relapsed, at a median of 10 months after HSCT. Four patients with continually low post-HSCT TLS-ERG levels (mostly <.01%) remained alive and in CR. The TLS-ERG levels of all 8 patients who relapsed were significantly increased before the relapse, exceeding 1.0% in all 7 patients who experienced hematologic relapse. In total, 7 patients received modified donor lymphocyte infusion (DLI), and 1 patient received IFN-α. All 7 patients with a TLS-ERG level >5.0% at the time of intervention experienced an increase or a brief decrease in TLS-ERG level, followed by an increase, and 6 relapsed, whereas the TLS-ERG level of 1 patient with a TLS-ERG level <1.0% at intervention decreased to undetectable. Therefore, t(16;21) AML is an indication for allo-HSCT. Among the HSCT recipients, 30.8% responded to treatment with CR. TLS-ERG transcript levels reflect MRD and might predict relapse and guide effective intervention.

Ge Z, Cheng Z, Yang X, et al.
Long noncoding RNA SchLAH suppresses metastasis of hepatocellular carcinoma through interacting with fused in sarcoma.
Cancer Sci. 2017; 108(4):653-662 [PubMed] Free Access to Full Article Related Publications
Emerging evidence has indicated that deregulation of long non-coding RNAs (lncRNAs) can contribute to the progression and metastasis of human cancer, including hepatocellular carcinoma (HCC). However, the roles of most lncRNAs in HCC remain largely unknown. Here we found a long noncoding RNA termed SchLAH (seven chromosome locus associated with HCC; also called BC035072) was generally downregulated in HCC. Low expression of SchLAH was significantly correlated with shorter overall survival of HCC patients. In vitro and in vivo assays indicated that overexpression of SchLAH inhibited the migration and lung metastasis of HCC cells. Knockdown of SchLAH by siRNA pool promoted the migration of HCC cells. RNA pull-down and RNA immunoprecipitation assays demonstrated SchLAH physically interacted with fused in sarcoma (FUS). PCR array analysis showed that RhoA and Rac1 were the downstream effector molecules of SchLAH during HCC metastasis. Knockdown of FUS rescued the mRNA levels of RhoA and Rac1 that were repressed by SchLAH. These results suggest that SchLAH may suppress the metastasis of HCC cells by interacting with FUS, which indicates potential of SchLAH for the prognosis and treatment of HCC.

Wang Z, Lei H, Sun Q
MicroRNA-141 and its associated gene FUS modulate proliferation, migration and cisplatin chemosensitivity in neuroblastoma cell lines.
Oncol Rep. 2016; 35(5):2943-51 [PubMed] Free Access to Full Article Related Publications
In the present study, a novel signaling pathway of microRNA-141 (miR-141)/fused in sarcoma (FUS) was investigated in neuroblastoma (NB). Gene expression of miR-141 was evaluated in 6 NB cell lines. IMR-32 and SH-SY5Y cells were transduced with the miR-141 mimic lentivirus. The effects of miR-141 upregulation on cell proliferation, cell division, migration, chemosensitivity and in vivo explants were evaluated by MTT, cell cycle, wound-healing, cisplatin sensitivity and in vivo tumor growth assays, respectively. The correlation between miR-141 and the FUS gene was evaluated by luciferase assay and qRT-PCR. FUS was also downregulated in IMR-32 and SH-SY5Y cells to evaluate its impact on NB regulation. miR-141 was downregulated in both MYCN‑ and non-MYCN‑amplified NB cell lines. In the IMR-32 and SH-SY5Y cells, lentivirus-induced miR-141 upregulation inhibited cancer proliferation, cell cycle progression, migration and increased cisplatin chemosensitivity in vitro. In addition, miR-141 upregulation reduced the in vivo growth of IMR-32 tumor explants. FUS was found to be inversely regulated by miR-141 in NB. Small interfering RNA (siRNA)-induced FUS downregulation had similar tumor-suppressive effects as miR-141 upregulation on NB cell proliferation, cell cycle progression, migration and cisplatin chemosensitivity. Our data indicate that miR-141 and the FUS gene, which are inversely correlated, play significant functional roles in regulating human NB.

Mazari PM, Weber KL, Kim S, Zhang PJ
Cytogenetically confirmed low-grade fibromyxoid sarcoma arising from the tibia.
Hum Pathol. 2016; 48:56-9 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma is a rare soft tissue tumor with a benign histologic appearance but comparatively aggressive clinical course. These discrepant features make it extremely important to diagnose early so that appropriate management can be initiated. This diagnosis often hinges on the presence of the hallmark cytogenetic aberration, a balanced 7;16 translocation resulting in a FUS-CREB3L2 fusion gene. Although this neoplasm most commonly arises in the deep soft tissue of the lower extremities, it has been reported to arise from a wide variety of sites including intraabdominal and intracranial locations. Only 1 previous study has described low-grade fibromyxoid sarcoma as arising from a bony site; however, cytogenetic and immunohistochemical confirmation was not available at that time. Herein, we describe the first ever cytogenetically confirmed case of low-grade fibromyxoid sarcoma arising as a primary bone tumor in the tibia of a 35-year-old woman.

Leduc C, Zhang L, Öz B, et al.
Thoracic Myoepithelial Tumors: A Pathologic and Molecular Study of 8 Cases With Review of the Literature.
Am J Surg Pathol. 2016; 40(2):212-23 [PubMed] Free Access to Full Article Related Publications
Thoracic myoepithelial tumors (MTs) are a rare group of tumors showing predominant or exclusive myoepithelial differentiation. They are poorly characterized from both a morphologic and genetic standpoint, in particular features that separate benign from malignant behavior. We examined the histologic and immunohistochemical features of 8 primary thoracic MTs and performed fluorescence in situ hybridization for EWSR1, FUS, PLAG1, and HMGA2, as well as several partner genes. Half (4/8) of the MTs occurred in large airways, and 3 had infiltrative borders. All cases showed immunoreactivity for epithelial markers, in conjunction with S100 protein or myogenic markers. MTs showed morphologic characteristics analogous to MTs at other sites, with no tumors having ductal differentiation. Necrosis and/or lymphovascular invasion was present in 5 cases, with mitotic activity ranging from 0 to 6 mitoses/2 mm² (mean 1). Metastases occurred in 2 cases, and no patients died of disease. Gene rearrangements were identified in half of the cases, with EWSR1-PBX1, EWSR1-ZNF444, and FUS-KLF17 fusions identified in 1 case each and 1 case having EWSR1 rearrangement with no partner identified. No cases were found to have HMGA2 or PLAG1 abnormalities. Compared with fusion-negative tumors, fusion-positive tumors tended to occur in patients who were younger (50 vs. 58 y), female (1:3 vs. 3:1 male:female ratio), and demonstrated predominantly spindle and clear cell morphology. Using a combined data set of our case series with 16 cases from the literature, poor prognosis was significantly correlated with metastases (P=0.003), necrosis (P=0.027), and ≥5 mitoses/2 mm²/10 high-power field (P=0.005). In summary, we identify a subset of thoracic MTs harboring rearrangements in EWSR1 or FUS, and our data suggest that necrosis and increased mitotic activity correlate with aggressive clinical behavior.

Colombrita C, Onesto E, Buratti E, et al.
From transcriptomic to protein level changes in TDP-43 and FUS loss-of-function cell models.
Biochim Biophys Acta. 2015; 1849(12):1398-410 [PubMed] Related Publications
The full definition of the physiological RNA targets regulated by TDP-43 and FUS RNA-binding proteins (RBPs) represents an important issue in understanding the pathogenic mechanisms associated to these two proteins in amyotrophic lateral sclerosis and frontotemporal dementia. In the last few years several high-throughput screenings have generated a plethora of data, which are difficult to compare due to the different experimental designs and models explored. In this study by using the Affymetrix Exon Arrays, we were able to assess and compare the effects of both TDP-43 and FUS loss-of-function on the whole transcriptome using the same human neuronal SK-N-BE cell model. We showed that TDP-43 and FUS depletion induces splicing and gene expression changes mainly distinct for the two RBPs, although they may regulate common pathways, including neuron differentiation and cytoskeleton organization as evidenced by functional annotation analysis. In particular, TDP-43 and FUS were found to regulate splicing and expression of genes related to neuronal (SEPT6, SULT4A1, TNIK) and RNA metabolism (DICER, ELAVL3/HuC, POLDIP3). Our extended analysis at protein level revealed that these changes have also impact on the protein isoform ratio and content, not always in a direct correlation with transcriptomic data. Contrarily to a loss-of-function mechanism, we showed that mutant TDP-43 proteins maintained their splicing activity in human ALS fibroblasts and experimental cell lines. Our findings further contribute to define the biological functions of these two RBPs in physiological and disease state, strongly encouraging the evaluation of the identified transcriptomic changes at protein level in neuronal experimental models.

Sotoca AM, Prange KH, Reijnders B, et al.
The oncofusion protein FUS-ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia.
Oncogene. 2016; 35(15):1965-76 [PubMed] Free Access to Full Article Related Publications
The ETS transcription factor ERG has been implicated as a major regulator of both normal and aberrant hematopoiesis. In acute myeloid leukemias harboring t(16;21), ERG function is deregulated due to a fusion with FUS/TLS resulting in the expression of a FUS-ERG oncofusion protein. How this oncofusion protein deregulates the normal ERG transcription program is unclear. Here, we show that FUS-ERG acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR:RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-trans retinoic acid treatment of t(16;21) cells as well as FUS-ERG knockdown alleviate the myeloid-differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.

Xin J, Zhang XK, Xin DY, et al.
FUS1 acts as a tumor-suppressor gene by upregulating miR-197 in human glioblastoma.
Oncol Rep. 2015; 34(2):868-76 [PubMed] Related Publications
Glioblastoma is the most common primary malignancy of the adult central nervous system (CNS) and is associated with an exceptionally poor prognosis. Elucidation of the pathogenesis and molecular changes will help us to further understand the pathogenesis and progression of the disease and offer new therapeutic targets. FUS1 (TUSC2, tumor suppressor candidate 2) is a tumor-suppressor gene located on human chromosome 3p21. Restoration of FUS1 function in human non-small cell lung cancer (NSCLC) cells was found to significantly inhibit tumor cell growth and modulate the chemosensitivity of lung cancer cells. Yet, its role in human glioblastoma has rarely been addressed. In the present study, we demonstrated that low expression of FUS1 was detected in high-grade human glioma, implying that FUS1 expression is negatively associated with progression of the disease. Subsequent studies confirmed that FUS1 overexpression inhibited the proliferation, migration and invasion of human glioblastoma cells. In addition, we found that FUS1 overexpression significantly upregulated miR-197 expression in the glioblastoma cells. We also revealed that miR-197 suppressed the proliferation, migration and invasion of the cells as well as the silencing of miR-197 attenuated the biological functions of FUS1. Using human glioblastoma tissue samples, we demonstrated that miR-197 is negatively associated with metastasis. All the results demonstrated that FUS1 acts as a tumor-suppressor gene by upregulating miR-197 in human glioblastoma and implied that restoration of FUS1 and miR-197 could be new therapeutic strategies for glioblastoma.

Thway K, Gonzalez D, Wren D, et al.
Angiomatoid fibrous histiocytoma: comparison of fluorescence in situ hybridization and reverse transcription polymerase chain reaction as adjunct diagnostic modalities.
Ann Diagn Pathol. 2015; 19(3):137-42 [PubMed] Related Publications
Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the extremities of children and young adults. Although it has characteristic histologic features of a lymphoid cuff surrounding nodules of ovoid cells with blood-filled cystic cavities, diagnosis is often difficult due to its morphologic heterogeneity and lack of specific immunoprofile. Angiomatoid fibrous histiocytoma is associated with recurrent chromosomal translocations, leading to characteristic EWSR1-CREB1, EWSR1-ATF1, and, rarely, FUS-ATF1 gene fusions; fluorescence in situ hybridization (FISH), detecting EWSR1 or FUS rearrangements, and reverse transcription-polymerase chain reaction (RT-PCR) for EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts have become routine ancillary tools. We present a large comparative series of FISH and RT-PCR for AFH. Seventeen neoplasms (from 16 patients) histologically diagnosed as AFH were assessed for EWSR1 rearrangements or EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts. All 17 were positive for either FISH or RT-PCR or both. Of 16, 14 (87.5%) had detectable EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts by RT-PCR, whereas 13 (76.5%) of 17 had positive EWSR1 rearrangement with FISH. All 13 of 13 non-AFH control neoplasms failed to show EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts, whereas EWSR1 rearrangement was present in 2 of these 13 cases (which were histopathologically myoepithelial neoplasms). This study shows that EWSR1-CREB1 or EWSR1-ATF1 fusions predominate in AFH (supporting previous reports that FUS rearrangement is rare in AFH) and that RT-PCR has a comparable detection rate to FISH for AFH. Importantly, cases of AFH can be missed if RT-PCR is not performed in conjunction with FISH, and RT-PCR has the added advantage of specificity, which is crucial, as EWSR1 rearrangements are present in a variety of neoplasms in the histologic differential diagnosis of AFH, that differ in behavior and treatment.

Ma J, Lin J, Qian J, et al.
MiR-378 promotes the migration of liver cancer cells by down-regulating Fus expression.
Cell Physiol Biochem. 2014; 34(6):2266-74 [PubMed] Related Publications
BACKGROUND: miR-378 regulates osteoblast differentiation and participates in tumor cell self-renewal and chemo-resistance. However, the function of miR-378 in liver cancer cell migration has not been reported to date.
METHODS: miR-378 expression was examined using real-time quantitative PCR. HepG2 cell migration and liver cell invasion were examined using wound-healing and cell invasion assays. Additionally, HepG2 cell metastasis was analyzed in nude mice.
RESULTS: miR-378 over-expression enhances HepG2 cell proliferation, migration and liver cell invasion. Typical metastatic lesions were found in the livers of mice injected with miR-378-transfected cells, and high levels of the CMV promoter were detected in the nodules, indicating that miR-378 promoted the metastasis of the tumor cells to the liver. We also demonstrated that miR-378 down-regulated Fus expression.
CONCLUSIONS: Our results suggested that miR-378 enhanced cell migration and metastasis by down-regulating Fus expression.

Campos-Melo D, Droppelmann CA, Volkening K, Strong MJ
RNA-binding proteins as molecular links between cancer and neurodegeneration.
Biogerontology. 2014; 15(6):587-610 [PubMed] Related Publications
For many years, epidemiological studies have suggested an association between cancer and neurodegenerative disorders-two disease processes that seemingly have little in common. Although these two disease processes share disruptions in a wide range of cellular pathways, including cell survival, cell death and the cell cycle, the end result is very divergent: uncontrolled cell survival and proliferation in cancer and progressive neuronal cell death in neurodegeneration. Despite the clinical data connecting these two disease processes, little is known about the molecular links between them. Among the mechanisms affected in cancer and neurodegenerative diseases, alterations in RNA metabolism are obtaining significant attention given the critical role for RNA transcription, maturation, transport, stability, degradation and translation in normal cellular function. RNA-binding proteins (RBPs) are integral to each stage of RNA metabolism through their participation in the formation of ribonucleoprotein complexes (RNPs). RBPs have a broad range of functions including posttranscriptional regulation of mRNA stability, splicing, editing and translation, mRNA export and localization, mRNA polyadenylation and miRNA biogenesis, ultimately impacting the expression of every single gene in the cell. In this review, we examine the evidence for RBPs as being key a molecular linkages between cancer and neurodegeneration.

Zhou H, Mangelsdorf M, Liu J, et al.
RNA-binding proteins in neurological diseases.
Sci China Life Sci. 2014; 57(4):432-44 [PubMed] Related Publications
Emerging studies support that RNA-binding proteins (RBPs) play critical roles in human biology and pathogenesis. RBPs are essential players in RNA processing and metabolism, including pre-mRNA splicing, polyadenylation, transport, surveillance, mRNA localization, mRNA stability control, translational control and editing of various types of RNAs. Aberrant expression of and mutations in RBP genes affect various steps of RNA processing, altering target gene function. RBPs have been associated with various diseases, including neurological diseases. Here, we mainly focus on selected RNA-binding proteins including Nova-1/Nova-2, HuR/HuB/HuC/HuD, TDP-43, Fus, Rbfox1/Rbfox2, QKI and FMRP, discussing their function and roles in human diseases.

Arbajian E, Puls F, Magnusson L, et al.
Recurrent EWSR1-CREB3L1 gene fusions in sclerosing epithelioid fibrosarcoma.
Am J Surg Pathol. 2014; 38(6):801-8 [PubMed] Related Publications
Sclerosing epithelioid fibrosarcoma (SEF) and low-grade fibromyxoid sarcoma (LGFMS) are 2 distinct types of sarcoma, with a subset of cases showing overlapping morphologic and immunohistochemical features. LGFMS is characterized by expression of the MUC4 protein, and about 90% of cases display a distinctive FUS-CREB3L2 gene fusion. In addition, SEF is often MUC4 positive, but is genetically less well studied. Fluorescence in situ hybridization (FISH) studies have shown involvement of the FUS gene in the majority of so-called hybrid LGFMS/SEF and in 10% to 25% of sarcomas with pure SEF morphology. In this study, we investigated a series of 10 primary tumors showing pure SEF morphology, 4 cases of LGFMS that at local or distant relapse showed predominant SEF morphology, and 1 primary hybrid LGFMS/SEF. All but 1 case showed diffuse expression for MUC4. Using FISH, reverse transcription polymerase chain reaction, and/or mRNA sequencing in selected cases, we found recurrent EWSR1-CREB3L1 fusion transcripts by reverse transcription polymerase chain reaction in 3/10 pure SEF cases and splits and deletions of the EWSR1 and/or CREB3L1 genes by FISH in 6 additional cases. All 5 cases of LGFMS with progression to SEF morphology or hybrid features had FUS-CREB3L2 fusion transcripts. Our results indicate that EWSR1 and CREB3L1 rearrangements are predominant over FUS and CREB3L2 rearrangements in pure SEF, highlighting that SEF and LGFMS are different tumor types, with different impacts on patient outcome.

Meng J, Majidi M, Fang B, et al.
The tumor suppressor gene TUSC2 (FUS1) sensitizes NSCLC to the AKT inhibitor MK2206 in LKB1-dependent manner.
PLoS One. 2013; 8(10):e77067 [PubMed] Free Access to Full Article Related Publications
TUSC2-defective gene expression is detected in the majority of lung cancers and is associated with worse overall survival. We analyzed the effects of TUSC2 re-expression on tumor cell sensitivity to the AKT inhibitor, MK2206, and explored their mutual signaling connections, in vitro and in vivo. TUSC2 transient expression in three LKB1-defective non-small cell lung cancer (NSCLC) cell lines combined with MK2206 treatment resulted in increased repression of cell viability and colony formation, and increased apoptotic activity. In contrast, TUSC2 did not affect the response to MK2206 treatment for two LKB1-wild type NSCLC cell lines. In vivo, TUSC2 systemic delivery, by nanoparticle gene transfer, combined with MK2206 treatment markedly inhibited growth of tumors in a human LKB1-defective H322 lung cancer xenograft mouse model. Biochemical analysis showed that TUSC2 transient expression in LKB1-defective NSCLC cells significantly stimulated AMP-activated protein kinase (AMPK) phosphorylation and enzymatic activity. More importantly, AMPK gene knockdown abrogated TUSC2-MK2206 cooperation, as evidenced by reduced sensitivity to the combined treatment. Together, TUSC2 re-expression and MK2206 treatment was more effective in inhibiting the phosphorylation and kinase activities of AKT and mTOR proteins than either single agent alone. In conclusion, these findings support the hypothesis that TUSC2 expression status is a biological variable that potentiates MK2206 sensitivity in LKB1-defective NSCLC cells, and identifies the AMPK/AKT/mTOR signaling axis as an important regulator of this activity.

Rodriguez R, Tornin J, Suarez C, et al.
Expression of FUS-CHOP fusion protein in immortalized/transformed human mesenchymal stem cells drives mixoid liposarcoma formation.
Stem Cells. 2013; 31(10):2061-72 [PubMed] Related Publications
Increasing evidence supports that mesenchymal stromal/stem cells (MSCs) may represent the target cell for sarcoma development. Although different sarcomas have been modeled in mice upon expression of fusion oncogenes in MSCs, sarcomagenesis has not been successfully modeled in human MSCs (hMSCs). We report that FUS-CHOP, a hallmark fusion gene in mixoid liposarcoma (MLS), has an instructive role in lineage commitment, and its expression in hMSC sequentially immortalized/transformed with up to five oncogenic hits (p53 and Rb deficiency, hTERT over-expression, c-myc stabilization, and H-RAS(v12) mutation) drives the formation of serially transplantable MLS. This is the first model of sarcoma based on the expression of a sarcoma-associated fusion protein in hMSC, and allowed us to unravel the differentiation processes and signaling pathways altered in the MLS-initiating cells. This study will contribute to test novel therapeutic approaches and constitutes a proof-of-concept to use hMSCs as target cell for modeling other fusion gene-associated human sarcomas.

Ferlosio A, Doldo E, Polisca P, Orlandi A
Low-grade fibromyxoid sarcoma: an unusual cardiac location.
Cardiovasc Pathol. 2013 May-Jun; 22(3):e15-7 [PubMed] Related Publications
We report the unusual cardiac localization of a primary low-grade fibromyxoid sarcoma of the right ventricle in a 57-year-old woman. Histological examination revealed a prevalent myxoid appearance with whorling growth pattern of small or spindle cells with bland features alternating with rare more collagenous hypocellular areas with rare atypical cells. Genomic polymerase chain reaction of genomic DNA revealed the typical FUS/Creb3L2 fusion gene products typical of low-grade fibromyxoid sarcoma. The tumor was surgically removed and recurred after 7 years as high-grade pleomorphic sarcoma. The patient died 6 months after the clinical manifestation of recurrence. Low-grade fibromyxoid sarcoma of soft tissues is a rare, distinctive variant of fibrosarcoma-typically arising in deep soft tissue of lower extremities and trunk-that rarely metastasizes. Clinically, low-grade fibromyxoid sarcoma is characterized by a longer survival rate compared to other sarcomas, suggesting its consideration in the differential diagnosis of cardiac tumors with a myxoid appearance.

Dobin SM, Malone VS, Lopez L, Donner LR
Unusual histologic variant of a low-grade fibromyxoid sarcoma in a 3-year-old boy with complex chromosomal translocations involving 7q34, 10q11.2, and 16p11.2 and rearrangement of the FUS gene.
Pediatr Dev Pathol. 2013 Mar-Apr; 16(2):86-90 [PubMed] Related Publications
Low-grade fibromyxoid sarcomas are rare, histologically deceptive, cytologically bland tumors that are infrequently encountered in pediatric patients. Our knowledge of histologic spectrum of these tumors is limited. A histologically unusual variant of a low-grade fibromyxoid sarcoma arising in a 3-year-old boy and containing islands of cohesive epithelioid cells is described. The diagnosis was, given the patient's age and the presence of epithelioid islands, very difficult and was verified by the presence of 3-way chromosomal translocations involving 7q34, 10q11.2, and 16p11.2 by rearrangement of the FUS gene and by immunoreactivity for mucin 4.

Borjigin N, Ohno S, Wu W, et al.
TLS-CHOP represses miR-486 expression, inducing upregulation of a metastasis regulator PAI-1 in human myxoid liposarcoma.
Biochem Biophys Res Commun. 2012; 427(2):355-60 [PubMed] Related Publications
Myxoid liposarcomas (MLSs) are characterized by t(12;16)(q13;p11) translocation and expression of TLS-CHOP chimeric oncoprotein. However, the molecular functions of TLS-CHOP have not been fully understood. On the other hand, microRNAs (miRNAs) comprise an abundant class of endogenous small non-coding RNAs that negatively regulate the expression of their target genes, and are involved in many biological processes. It is now evident that dysregulation of miRNAs is an important step in the development of many cancers. To our knowledge, however, there have been no reports of the miRNAs involved in MLS tumorigenesis and development. In this study, we have found that miR-486 expression was repressed in TLS-CHOP-expressed NIH3T3 fibroblasts and MLS tissues, and exogenous overexpression of miR-486 repressed growth of MLS cells. Thus, downregulation of miR-486 may be an important process for MLS. In addition, we have identified plasminogen activator inhibitor-1 (PAI-1) as a novel target gene of miR-486. PAI-1 is a unique type of serine protease inhibitor and is known to be one of the key regulators of tumor invasion and metastasis. Furthermore, knockdown of PAI-1 by a specific small interfering RNA (siRNA) inhibited growth of MLS cells, suggesting that increased expression of PAI-1 by miR-486 repression is critical for survival of MLS cells. Collectively, these results suggest a novel essential molecular mechanism that TLS-CHOP activates PAI-1 expression by repression of miR-486 expression in MLS tumorigenesis and development.

Doyle LA, Wang WL, Dal Cin P, et al.
MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement.
Am J Surg Pathol. 2012; 36(10):1444-51 [PubMed] Related Publications
Sclerosing epithelioid fibrosarcoma (SEF) is a rare aggressive fibroblastic neoplasm composed of cords of epithelioid cells embedded in a dense collagenous stroma. The reported immunophenotype of SEF is nonspecific. Some SEF cases show morphologic and molecular overlap with low-grade fibromyxoid sarcoma (LGFMS), suggesting a relationship between these tumor types. MUC4 has recently been identified as a sensitive and specific marker for LGFMS; MUC4 expression was also observed in 2 tumors with hybrid features of SEF and LGFMS. We investigated MUC4 expression in SEF and other epithelioid soft tissue tumors to determine (1) the potential diagnostic utility of MUC4 for SEF and (2) the association between MUC4 expression and FUS rearrangement in SEF. Whole sections of 180 tumors were evaluated: 41 cases of SEF (including 29 "pure" SEF and 12 hybrid LGFMS-SEF), 20 epithelioid sarcomas, 11 clear cell sarcomas, 11 metastatic melanomas, 10 perivascular epithelioid cell tumors, 10 alveolar soft part sarcomas, 10 epithelioid angiosarcomas, 10 epithelioid hemangioendotheliomas, 10 epithelioid gastrointestinal stromal tumors, 10 myoepithelial carcinomas, 17 ossifying fibromyxoid tumors, 10 leiomyosarcomas, and 10 biphasic synovial sarcomas. Immunohistochemical analysis was performed after antigen retrieval using a mouse anti-MUC4 monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed on 33 SEF cases using FUS break-apart probes. A subset of cases was also evaluated for EWSR1 and CREB3L2/L1 rearrangements by FISH. Strong diffuse cytoplasmic staining for MUC4 was observed in 32 of 41 (78%) cases of SEF, including all 12 hybrid tumors. FUS rearrangement was detected in 8 of 21 (38%) MUC4-positive cases of SEF with successful FISH studies. The prevalence of FUS rearrangement was similar in hybrid LGFMS-SEF (2 of 6; 33%) and SEF without an LGFMS component (6 of 15; 40%). FUS rearrangement was not detected in any cases of MUC4-negative SEF. Two hybrid tumors had both EWSR1 and CREB3L1 rearrangements. MUC4 expression was also seen in 9 of 10 (90%) biphasic synovial sarcomas, predominantly in the glandular component. All other tumor types were negative for MUC4, apart from focal reactivity in 5 ossifying fibromyxoid tumors, 2 epithelioid gastrointestinal stromal tumors, and 1 myoepithelial carcinoma. MUC4 is a sensitive and relatively specific marker for SEF among epithelioid soft tissue tumors. MUC4 expression occurs more frequently than FUS rearrangement in SEF. The finding of EWSR1 and CREB3L1 rearrangements in 2 cases of hybrid LGFMS-SEF suggests that SEFs are genetically heterogenous. MUC4-positive SEFs with FUS rearrangement are likely closely related to LGFMS. MUC4-positive SEFs that lack FUS rearrangement may be related to LGFMS but could have alternate fusion partners, including EWSR1. SEF without MUC4 expression may represent a distinct group of tumors. MUC4 expression correlates with glandular epithelial differentiation in biphasic synovial sarcoma and is very limited in other epithelioid soft tissue tumors.

Wang WL, Evans HL, Meis JM, et al.
FUS rearrangements are rare in 'pure' sclerosing epithelioid fibrosarcoma.
Mod Pathol. 2012; 25(6):846-53 [PubMed] Related Publications
Several recent reports have described low-grade fibromyxoid sarcoma with sclerosing epithelioid fibrosarcoma-like areas. We evaluated cases of pure sclerosing epithelioid fibrosarcoma lacking areas of low-grade fibromyxoid sarcoma for FUS rearrangement to determine whether this entity could be related to low-grade fibromyxoid sarcoma. Available formalin-fixed paraffin-embedded tissue of 27 sclerosing epithelioid fibrosarcoma from 25 patients was retrieved and tabulated with clinical information. Unstained slides from formalin-fixed paraffin-embedded blocks were prepared and fluorescence in-situ hybridization was performed using a commercial FUS break-apart probe. The median patient age at presentation was 50 (range, 14-78) years, with 14 males and 10 females. Sclerosing epithelioid fibrosarcoma most commonly involved the extremities (n=8) or chest (n=6). Sixteen patients had a median follow-up of 17 (range, 1-99) months; seven were alive and well at 12 (range, 5-30) months; three alive with disease at 28 (range, 9-99) months; five dead of disease at a median of 22 (range, 1-36) months and one was dead of unknown causes. Twelve patients were known to have metastases; the most common site was lung (n=7), followed by bone (n=3), lymph nodes (n=2) and peritoneum (n=1). Only 2 of 22 (9%) analyzable cases of sclerosing epithelioid fibrosarcoma showed rearrangement in the FUS locus by fluorescence in-situ hybridization. Although cytogenetically confirmed low-grade fibromyxoid sarcoma can have sclerosing epithelioid fibrosarcoma-like areas, FUS rearrangement, which is characteristic of low-grade fibromyxoid sarcoma, appears to be relatively rare in pure sclerosing epithelioid fibrosarcoma.

Uboldi S, Bernasconi S, Romano M, et al.
Characterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents.
Int J Cancer. 2012; 131(1):59-69 [PubMed] Related Publications
Myxoid Liposarcomas (MLS), characterized by the expression of FUS-CHOP fusion gene are clinically very sensitive to the DNA binding antitumor agent, trabectedin. However, resistance eventually occurs, preventing disease eradication. To investigate the mechanisms of resistance, a trabectedin resistant cell line, 402-91/ET, was developed. The resistance to trabectedin was not related to the expression of MDR related proteins, uptake/efflux of trabectedin or GSH levels that were similar in parental and resistant cells. The 402-91/ET cells were hypersensitive to UV light because of a nucleotide excision repair defect: XPG complementation decreased sensitivity to UV rays, but only partially to trabectedin. 402-91/ET cells showed collateral sensitivity to temozolomide due to the lack of O(6) -methylguanine-DNA-methyltransferase (MGMT) activity, related to the hypermethylation of MGMT promoter. In 402-91 cells chromatin immunoprecipitation (ChIP) assays showed that FUS-CHOP was bound to the PTX3 and FN1 gene promoters, as previously described, and trabectedin caused FUS-CHOP detachment from DNA. Here we report that, in contrast, in 402-91/ET cells, FUS-CHOP was not bound to these promoters. Differences in the modulation of transcription of genes involved in different pathways including signal transduction, apoptosis and stress response between the two cell lines were found. Trabectedin activates the transcription of genes involved in the adipogenic-program such as c/EBPα and β, in 402-91 but not in 402-91/ET cell lines. The collateral sensitivity of 402-91/ET to temozolomide provides the rationale to investigate the potential use of methylating agents in MLS patients resistant to trabectedin.

Flucke U, Palmedo G, Blankenhorn N, et al.
EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases.
Mod Pathol. 2011; 24(11):1444-50 [PubMed] Related Publications
Cutaneous myoepithelial tumors form a clinicopathological spectrum ranging from mixed tumor to myoepithelioma and myoepithelial carcinoma. Recently, EWSR1 rearrangement has been described in a subset of soft tissue myoepithelial tumors, whereas the cutaneous counterparts showed this aberration in a minority of cases. This raises the question whether cutaneous myoepithelial tumors have comparable genetic alterations. We examined 18 cases of cutaneous myoepithelial tumors arising in 7 female and 11 male patients (age range, 34-86 years; mean, 58 years). Eight mixed tumors occurred at the head, and one at the scrotum. Six myoepitheliomas arose at the extremities, and one case each at the back and head. One myoepithelial carcinoma occurred at the cheek. The tumor size ranged from 0.3 to 1.7 cm (mean, 1.0 cm). All mixed tumors and three myoepitheliomas were limited to the dermis. Four myoepitheliomas and the myoepithelial carcinoma involved the subcutis. Mixed tumors and myoepitheliomas were composed of myoepithelial cells with a variable cytomorphology, architecture and stromal background. Ductal structures were seen by definition in mixed tumors. The myoepithelial carcinoma represented an infiltrative dermal neoplasm consisting of atypical spindle cells. Immunohistochemically, all cases tested were positive for EMA and calponin, whereas S100, CK, ASMA and GFAP were expressed in 90%, 80%, 78% and 50% of the cases tested, respectively. By fluorescent in situ hybridization analysis, 7 out of 16 cases (44%) exhibited EWSR1 rearrangement. Four of them were mixed tumors, two were myoepitheliomas and one was a myoepithelial carcinoma, confirming that these lesions represent a spectrum of dermal myoepithelial tumors. Follow-up information, available for five patients (including the patient with a myoepithelial carcinoma), revealed no evidence of disease in all cases (range, 6-72 months). Our study provides a genetic relationship of myoepithelial tumors of the skin with their counterparts in soft tissue, bone and visceral localization by sharing EWSR1 rearrangement.

Rose B, Tamvakopoulos GS, Dulay K, et al.
The clinical significance of the FUS-CREB3L2 translocation in low-grade fibromyxoid sarcoma.
J Orthop Surg Res. 2011; 6:15 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue neoplasm with a deceptively benign histological appearance. Local recurrences and metastases can manifest many years following excision. The FUS-CREB3L2 gene translocation, which occurs commonly in LGFMS, may be detected by reverse-transcriptase polymerase chain reaction (RT-PCR) and fluorescence in situ hybridisation (FISH). We assessed the relationship between clinical outcome and translocation test result by both methods.
METHODS: We report genetic analysis of 23 LGFMS cases and clinical outcomes of 18 patients with mean age of 40.6 years. During follow-up (mean 24.8 months), there were no cases of local recurrence or metastasis. One case was referred with a third recurrence of a para-spinal tumour previously incorrectly diagnosed as a neurofibroma.
RESULTS: Results showed 50% of cases tested positive for the FUS-CREB3L2 translocation by RT-PCR and 81.8% by FISH, suggesting FISH is more sensitive than RT-PCR for confirming LGFMS diagnosis. Patients testing positive by both methods tended to be younger and had larger tumours. Despite this, there was no difference in clinical outcome seen during short and medium-term follow-up.
CONCLUSIONS: RT-PCR and FISH for the FUS-CREB3L2 fusion transcript are useful tools for confirming LGFMS diagnosis, but have no role in predicting medium-term clinical outcome. Due to the propensity for late recurrence or metastasis, wide excision is essential, and longer-term follow-up is required. This may identify a difference in long-term clinical outcome between translocation-positive and negative patients.

Patel RM, Downs-Kelly E, Dandekar MN, et al.
FUS (16p11) gene rearrangement as detected by fluorescence in-situ hybridization in cutaneous low-grade fibromyxoid sarcoma: a potential diagnostic tool.
Am J Dermatopathol. 2011; 33(2):140-3 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) is a rare, typically deep-seated soft tissue neoplasm with deceptively bland cytology and metastatic potential. A t(7;16)(q34;p11) translocation, yielding a FUS/CREB3L2 fusion gene, has been identified in approximately 80%-90% of deep soft tissue LGFMS. Cutaneous fibromyxoid neoplasms occur not infrequently; dermatopathologists rarely consider LGFMS in the differential diagnosis, as this lesion is uncommon in the skin. We identified a group of superficial LGFMS and a spectrum of other cutaneous fibromyxoid neoplasms and performed fluorescence in situ hybridization (FISH) to assess the frequency of FUS rearrangement. FISH for the chromosomal rearrangement of FUS (16p11), using a dual-color, break-apart probe (Abbott Molecular/Vysis, Des Plaines, IL), was performed on formalin-fixed paraffin-embedded tissue sections from superficial LGFMS (n = 6), myxomas (n = 10), and myxofibrosarcoma/myxoid malignant fibrous histiocytomas (myxoid MFH) (n = 5). One hundred nonoverlapping tumor nuclei per case were evaluated for either fused (normal) or split (translocated) signals. Of the LGFMS, 4 of 6 (67%) showed a rearrangement of FUS (range: 72%-80% positive nuclei per 100 nuclei). The other neoplasms within the differential diagnosis were devoid of any rearrangement involving FUS (range: 0%-2% positive nuclei per 100 nuclei). Our observed frequency of FUS rearrangement in superficial LGFMS is consistent with those published in the literature for more deeply seated lesions. When applied to suspicious superficial myxoid or fibromyxoid neoplasms, the FUS FISH probe in formalin-fixed paraffin-embedded tissue can be a useful ancillary technique for diagnosis of this uncommon and deceptively bland tumor.

Higuchi M, Suzuki H, Shio Y, et al.
Successfully resected intrathoracic low-grade fibromyxoid sarcoma.
Gen Thorac Cardiovasc Surg. 2010; 58(7):348-51 [PubMed] Related Publications
A low-grade fibromyxoid sarcoma (LGFMS), an Evans tumor, is highly unusual. It is rarely described as a primary neoplasm in the thoracic cavity. We experienced a case of a 20-year-old woman with a right intrathoracic tumor that was surgically treated. Postoperative pathology of the resected specimen revealed the tumor to be LGFMS based on its histological appearance, immunohistological staining, and evidence of fused in sarcoma (FUS) translocation by fluorescence in situ hybridization. Tumor resection was performed with a free surgical margin, and the resultant chest wall defect was repaired using prosthetic mesh. The patient has been well without any recurrence for 18 months since surgery.

Andersson MK, Göransson M, Olofsson A, et al.
Nuclear expression of FLT1 and its ligand PGF in FUS-DDIT3 carrying myxoid liposarcomas suggests the existence of an intracrine signaling loop.
BMC Cancer. 2010; 10:249 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The FUS-DDIT3 fusion oncogene encodes an abnormal transcription factor that has a causative role in the development of myxoid/round-cell liposarcomas (MLS/RCLS). We have previously identified FLT1 (VEGFR1) as a candidate downstream target gene of FUS-DDIT3. The aim of this study was to investigate expression of FLT1 and its ligands in MLS cells.
METHODS: HT1080 human fibrosarcoma cells were transiently transfected with FUS-DDIT3-GFP variant constructs and FLT1 expression was measured by quantitative real-time PCR. In addition, FLT1, PGF, VEGFA and VEGFB expression was measured in MLS/RCLS cell lines, MLS/RCLS tumors and in normal adiopocytes. We analyzed nine cases of MLS/RCLS and one cell line xenografted in mice for FLT1 protein expression using immunohistochemistry. MLS/RCLS cell lines were also analyzed for FLT1 by immunofluorescence and western blot. MLS/RCLS cell lines were additionally treated with FLT1 tyrosine kinase inhibitors and assayed for alterations in proliferation rate.
RESULTS: FLT1 expression was dramatically increased in transfected cells stably expressing FUS-DDIT3 and present at high levels in cell lines derived from MLS. The FLT1 protein showed a strong nuclear expression in cells of MLS tissue as well as in cultured MLS cells, which was confirmed by cellular fractionation. Tissue array analysis showed a nuclear expression of the FLT1 protein also in several other tumor and normal cell types including normal adipocytes. The FLT1 ligand coding gene PGF was highly expressed in cultured MLS cells compared to normal adipocytes while the other ligand genes VEGFA and VEGFB were expressed to lower levels. A more heterogeneous expression pattern of these genes were observed in tumor samples. No changes in proliferation rate of MLS cells were detected at concentrations for which the kinase inhibitors have shown specific inhibition of FLT1.
CONCLUSIONS: Our results imply that FLT1 is induced as an indirect downstream effect of FUS-DDIT3 expression in MLS. This could be a consequence of the ability of FUS-DDIT3 to hijack parts of normal adipose tissue development and reprogram primary cells to a liposarcoma-like phenotype. The findings of nuclear FLT1 protein and expression of corresponding ligands in MLS and normal tissues may have implications for tissue homeostasis and tumor development through auto- or intracrine signaling.

Matsumura T, Yamaguchi T, Tochigi N, et al.
Angiomatoid fibrous histiocytoma including cases with pleomorphic features analysed by fluorescence in situ hybridisation.
J Clin Pathol. 2010; 63(2):124-8 [PubMed] Related Publications
BACKGROUND: Angiomatoid fibrous histiocytoma (AFH) is a rare soft-tissue tumour of uncertain differentiation and low metastatic potential. Cytogenetics and/or molecular genetics have revealed that most have a rearrangement of the EWSR1 gene, whereas a FUS gene rearrangement is present in a minority of cases. Although some cases of AFH display striking pleomorphism and mitotic activity, there are no known clinical, morphological or genetic factors that predict metastasis. The authors present clinicopathological features of AFH, including cases showing a pleomorphic histological appearance, and results of fluorescence in situ hybridisation analysis of EWSR1 and FUS rearrangements.
METHODS: Tumour samples from 10 patients were subjected to clinicopathological and immunohistochemical analysis and dual-colour fluorescence in situ hybridisation for EWSR1 and FUS with split-signal probes.
RESULTS: All cases showed clinical features (sites: extremities followed by trunk; age: adolescent to young adult), morphology (multinodular proliferation of spindle cells, lymphoid cuffs and pseudovascular spaces) and immunohistochemical results (more than half were positive for CD68, CD99, desmin and epithelial membrane antigen) typical of AFH. There were two local recurrences in each of two patients. Two patients developed distant metastases and died from the disease; tumours of these two patients showed focal proliferation of large pleomorphic cells with hyperchromatic nuclei and high proliferative activity (>10/10 high-power field and Ki-67 labelling index >10%). There were no clinical, histological or immunohistochemical differences between the nine cases with EWSR1 rearrangement and one case with FUS rearrangement.
CONCLUSIONS: Wide surgical excision and careful follow-up are necessary for patients with AFH in view of its risk of local recurrence and metastasis leading to a fatal outcome.

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