CREB3L2

Gene Summary

Gene:CREB3L2; cAMP responsive element binding protein 3 like 2
Aliases: BBF2H7
Location:7q33
Summary:This gene encodes a member of the oasis bZIP transcription factor family. Members of this family can dimerize but form homodimers only. The encoded protein is a transcriptional activator. Translocations between this gene on chromosome 7 and the gene fused in sarcoma on chromosome 16 can be found in some tumors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclic AMP-responsive element-binding protein 3-like protein 2
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 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.

  • Chromosome 7
  • Immunohistochemistry
  • Gene Rearrangement
  • RNA-Binding Proteins
  • Childhood Cancer
  • Nerve Tissue Proteins
  • Gene Fusion
  • Signal Transduction
  • RNA-Binding Protein FUS
  • Soft Tissue Sarcoma
  • Sequence Analysis, RNA
  • Epithelioid Cells
  • Differential Diagnosis
  • Transcription Factor CHOP
  • Basic-Leucine Zipper Transcription Factors
  • Chromosome 16
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • rho GTP-Binding Proteins
  • Young Adult
  • Fibroma
  • Sensitivity and Specificity
  • Skin Cancer
  • Transcription Factors
  • FISH
  • Molecular Sequence Data
  • Fibrosarcoma
  • Soft Tissue Cancers
  • Up-Regulation
  • RTPCR
  • Oncogene Fusion Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Messenger RNA
  • Sclerosis
  • Adolescents
  • MUC4
  • Calmodulin-Binding Proteins
  • Base Sequence
  • Neoplasm Grading
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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

Entity Topic PubMed Papers
Soft Tissue SarcomaCREB3L2 and Soft Tissue Cancers View Publications14
Skin CancerCREB3L2 and Skin Cancer View Publications1
Soft Tissue Sarcomat(7;16)(q33;p11) FUS-CREB3L2 in Low-grade fibromyxoid sarcoma

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

Latest Publications: CREB3L2 (cancer-related)

He P, Sun L, Zhu D, et al.
Knock-Down of Endogenous Bornavirus-Like Nucleoprotein 1 Inhibits Cell Growth and Induces Apoptosis in Human Oligodendroglia Cells.
Int J Mol Sci. 2016; 17(4):435 [PubMed] Free Access to Full Article Related Publications
Endogenous bornavirus-like nucleoprotein elements (EBLNs) have been discovered in the genomes of various animals including humans, whose functions have been seldom studied. To explore the biological functions of human EBLNs, we constructed a lentiviral vector expressing a short-hairpin RNA against human EBLN1, which successfully inhibited EBLN1 expression by above 80% in infected human oligodendroglia cells (OL cells). We found that EBLN1 silencing suppressed cell proliferation, induced G2/M phase arrest, and promoted apoptosis in OL cells. Gene expression profiling demonstrated that 1067 genes were up-regulated, and 2004 were down-regulated after EBLN1 silencing. The top 10 most upregulated genes were PI3, RND3, BLZF1, SOD2, EPGN, SBSN, INSIG1, OSMR, CREB3L2, and MSMO1, and the top 10 most-downregulated genes were KRTAP2-4, FLRT2, DIDO1, FAT4, ESCO2, ZNF804A, SUV420H1, ZC3H4, YAE1D1, and NCOA5. Pathway analysis revealed that these differentially expressed genes were mainly involved in pathways related to the cell cycle, the mitogen-activated protein kinase pathway, p53 signaling, and apoptosis. The gene expression profiles were validated by using quantitative reverse transcription polymerase chain reaction (RT-PCR) for detecting these 20 most-changed genes. Three genes closely related to glioma, RND3, OSMR, and CREB3L2, were significantly upregulated and might be the key factors in EBLN1 regulating the proliferation and apoptosis of OL cells. This study provides evidence that EBLN1 plays a key role in regulating cell life and death, thereby opening several avenues of investigation regarding EBLN1 in the future.

Chien YC, Károlyi K, Kovács I
Paravertebral Low-grade Fibromyxoid Sarcoma with Supernumerary Ring Chromosome: Case Report and Literature Review.
Ann Clin Lab Sci. 2016; 46(1):90-6 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue neoplasm with a deceptively benign histological appearance and low-grade malignant potential which is often mistaken for other reactive or benign lesions. It most frequently harbors balanced t(7;16) translocation, and leads to the fusion of the FUS and CREB3L2 genes which can be detected by cytogenetic methods. Young adults are most commonly affected and it typically arises in the deep proximal extremities or trunk with frequent recurrences. It may metastasize to the lungs several years later. Paravertebral LGFMS is exceedingly rare and only few cases have been published in the literature. In those cases the novel immunohistochemical markers and cytogenetic studies were not performed and morphological mimickers could not be confidently excluded.We present a rare case of paravertebral LGFMS from a 54-years-old male patient, which previously was misdiagnosed as a neurofibroma with subsequent tumor recurrence. The concrete diagnosis was established by using MUC4 immunohistochemical stain and fluorescent in situ hybridization (FISH), which showed diffuse membranous positivity and supernumerary ring chromosome with unbalanced FUS gene rearrangement, respectively. The latter finding is also rare and may cause diagnostic dilemma if one is not aware of such uncommon, but well-documented phenomenon. Differential diagnosis with other low-grade spindle cell tumors will also be discussed along with the literature review.

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.

Cowan ML, Thompson LD, Leon ME, Bishop JA
Low-Grade Fibromyxoid Sarcoma of the Head and Neck: A Clinicopathologic Series and Review of the Literature.
Head Neck Pathol. 2016; 10(2):161-6 [PubMed] Free Access to Full Article Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) is a deceptively bland malignancy with potential for late recurrence and metastasis, which usually occurs in the deep soft tissues of the extremities and trunk. Most LGFMSs harbor a characteristic gene fusion of FUS-CREB3L2, and recently MUC4 immunostaining has been found to be highly sensitive and specific for the diagnosis. We present a dedicated series of head and neck LGFMS, including the first reported laryngeal case, as well as a review of reported head and neck cases. The surgical pathology archives of our three institutions were searched for cases of LGFMS arising within the head and neck, and four cases were identified. The H&E slides were reviewed, and immunohistochemistry were performed for pancytokeratin, p63, p40, EMA, S100 protein, β-catenin, actin, CD34, and MUC4. The patients were 6, 43, 45, and 73 years old (mean 41.8 years) and included three males and one female. The tumors were located in the posterior cervical spine, facial skin, mandible, and larynx. The tumors were treated with surgical excision, and all four had histologic features typical for LGFMS including alternating myxoid and fibrous areas with prominent curvilinear vasculature. All tumors were MUC4 positive (100%), 2/4 (50%) were p63 positive, 1/4 (25%) showed focal EMA positivity; all 4 were negative for pancytokeratin, p40, S100 protein, β-catenin, actin, and CD34. LGFMS is a low grade sarcoma that rarely develops in the head and neck. Due to its rarity, a pathologist may not consider LGFMS in the differential diagnosis of spindle cell neoplasms within the head and neck. Immunohistochemical staining is helpful, but stains should be selected carefully to avoid misdiagnosis.

Thway K, Ng W, Benson C, et al.
DOG1 Expression in Low-Grade Fibromyxoid Sarcoma: A Study of 11 Cases, With Molecular Characterization.
Int J Surg Pathol. 2015; 23(6):454-60 [PubMed] Related Publications
DOG1 is a highly sensitive marker for gastrointestinal stromal tumor (GIST) and is in the routine diagnostic antibody repertoire of many surgical pathology laboratories. Moreover, GIST is well recognized by both pathologists and clinicians in the differential diagnosis of intra-abdominal and pelvic neoplasms. Low-grade fibromyxoid sarcoma (LGFMS) is, however, much less frequently anticipated, particularly when occurring at unusual sites, because of its rarity and bland histology, particularly on core biopsy. We describe a case of a 53-year-old male with a large pelvic and pararectal mass, which on biopsy showed a moderately cellular spindle cell neoplasm within fibrous stroma. Immunohistochemistry at the referring center showed diffuse and strong expression of DOG1 with negativity for other markers. After referral to a tertiary center, repeat DOG1 immunohistochemistry again showed diffuse expression, but MUC4 was also positive, and this was confirmed to be LGFMS, harboring FUS-CREB3L2 fusion transcripts by reverse transcription-polymerase chain reaction and FUS rearrangement with fluorescence in situ hybridization. In view of this we assessed DOG1 expression in 10 other LGFMS (all MUC4 positive, and 9 molecularly confirmed to harbor FUS-CREB3L2 fusion transcripts and/or FUS or EWSR1 gene rearrangement), of which 5 showed DOG1 expression in up to 75% of tumor cells, varying in intensity from weak to strong. While LGFMS and GIST are generally morphologically dissimilar, less typical variants of each exist, and both can contain bland spindled cells within fibrous stroma. As the morphologic spectrum of LGFMS is wide, and as it can occur in unusual sites and may not be well recognized by general pathologists and non-soft tissue pathologists, we highlight the potential for diagnostic confusion with GIST owing to aberrant DOG1 expression. This is clinically pertinent, as the management and prognosis of these 2 neoplasms differs significantly.

Fűri I, Kalmár A, Wichmann B, et al.
Cell Free DNA of Tumor Origin Induces a 'Metastatic' Expression Profile in HT-29 Cancer Cell Line.
PLoS One. 2015; 10(7):e0131699 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epithelial cells in malignant conditions release DNA into the extracellular compartment. Cell free DNA of tumor origin may act as a ligand of DNA sensing mechanisms and mediate changes in epithelial-stromal interactions.
AIMS: To evaluate and compare the potential autocrine and paracrine regulatory effect of normal and malignant epithelial cell-related DNA on TLR9 and STING mediated pathways in HT-29 human colorectal adenocarcinoma cells and normal fibroblasts.
MATERIALS AND METHODS: DNA isolated from normal and tumorous colonic epithelia of fresh frozen surgically removed tissue samples was used for 24 and 6 hour treatment of HT-29 colon carcinoma and HDF-α fibroblast cells. Whole genome mRNA expression analysis and qRT-PCR was performed for the elements/members of TLR9 signaling pathway. Immunocytochemistry was performed for epithelial markers (i.e. CK20 and E-cadherin), DNA methyltransferase 3a (DNMT3a) and NFκB (for treated HDFα cells).
RESULTS: Administration of tumor derived DNA on HT29 cells resulted in significant (p<0.05) mRNA level alteration in 118 genes (logFc≥1, p≤0.05), including overexpression of metallothionein genes (i.e. MT1H, MT1X, MT1P2, MT2A), metastasis-associated genes (i.e. TACSTD2, MACC1, MALAT1), tumor biomarker (CEACAM5), metabolic genes (i.e. INSIG1, LIPG), messenger molecule genes (i.e. DAPP, CREB3L2). Increased protein levels of CK20, E-cadherin, and DNMT3a was observed after tumor DNA treatment in HT-29 cells. Healthy DNA treatment affected mRNA expression of 613 genes (logFc≥1, p≤0.05), including increased expression of key adaptor molecules of TLR9 pathway (e.g. MYD88, IRAK2, NFκB, IL8, IL-1β), STING pathway (ADAR, IRF7, CXCL10, CASP1) and the FGF2 gene.
CONCLUSIONS: DNA from tumorous colon epithelium, but not from the normal epithelial cells acts as a pro-metastatic factor to HT-29 cells through the overexpression of pro-metastatic genes through TLR9/MYD88 independent pathway. In contrast, DNA derived from healthy colonic epithelium induced TLR9 and STING signaling pathway in normal fibroblasts.

Iwamoto H, Matsuhisa K, Saito A, et al.
Promotion of Cancer Cell Proliferation by Cleaved and Secreted Luminal Domains of ER Stress Transducer BBF2H7.
PLoS One. 2015; 10(5):e0125982 [PubMed] Free Access to Full Article Related Publications
BBF2H7 is an endoplasmic reticulum (ER)-resident transmembrane basic leucine zipper (bZIP) transcription factor that is cleaved at the transmembrane domain by regulated intramembrane proteolysis in response to ER stress. The cleaved cytoplasmic N-terminus containing transcription activation and bZIP domains translocates into the nucleus to promote the expression of target genes. In chondrocytes, the cleaved luminal C-terminus is extracellularly secreted and facilitates proliferation of neighboring cells through activation of Hedgehog signaling. In the present study, we found that Bbf2h7 expression levels significantly increased by 1.070-2.567-fold in several tumor types including glioblastoma compared with those in respective normal tissues, using the ONCOMINE Cancer Profiling Database. In some Hedgehog ligand-dependent cancer cell lines including glioblastoma U251MG cells, the BBF2H7 C-terminus was secreted from cells into the culture media and promoted cancer cell proliferation through activation of Hedgehog signaling. Knockdown of Bbf2h7 expression suppressed the proliferation of U251MG cells by downregulating Hedgehog signaling. The impaired cell proliferation and Hedgehog signaling were recovered by addition of BBF2H7 C-terminus to the culture medium of Bbf2h7-knockdown U251MG cells. These data suggest that the secreted luminal BBF2H7 C-terminus is involved in Hedgehog ligand-dependent cancer cell proliferation through activation of Hedgehog signaling. Thus, the BBF2H7 C-terminus may be a novel target for the development of anticancer drugs.

Hofvander J, Tayebwa J, Nilsson J, et al.
RNA sequencing of sarcomas with simple karyotypes: identification and enrichment of fusion transcripts.
Lab Invest. 2015; 95(6):603-9 [PubMed] Related Publications
Gene fusions are neoplasia-associated mutations arising from structural chromosomal rearrangements. They have a strong impact on tumor development and constitute important diagnostic markers. Malignant soft tissue tumors (sarcomas) constitute a heterogeneous group of neoplasms with >50 distinct subtypes, each of which is rare. In addition, there is considerable morphologic overlap between sarcomas and benign lesions. Several subtypes display distinct gene fusions, serving as excellent biomarkers. The development of methods for deep sequencing of the complete transcriptome (RNA-Seq) has substantially improved the possibilities for detecting gene fusions. With the aim of identifying new gene fusions of biological and clinical relevance, eight sarcomas with simple karyotypes, ie, only one or a few structural rearrangements, were subjected to massively parallel paired-end sequencing of mRNA. Three different algorithms were used to identify fusion transcripts from RNA-Seq data. Three novel (KIAA2026-NUDT11, CCBL1-ARL1, and AFF3-PHF1) and two previously known fusions (FUS-CREB3L2 and HAS2-PLAG1) were found and could be verified by other methods. These findings show that RNA-Seq is a powerful tool for detecting gene fusions in sarcomas but also suggest that it is advisable to use more than one algorithm to analyze the output data as only two of the confirmed fusions were reported by more than one of the gene fusion detection software programs. For all of the confirmed gene fusions, at least one of the genes mapped to a chromosome band implicated by the karyotype, suggesting that sarcomas with simple karyotypes constitute an excellent resource for identifying novel gene fusions.

Prieto-Granada C, Zhang L, Chen HW, et al.
A genetic dichotomy between pure sclerosing epithelioid fibrosarcoma (SEF) and hybrid SEF/low-grade fibromyxoid sarcoma: a pathologic and molecular study of 18 cases.
Genes Chromosomes Cancer. 2015; 54(1):28-38 [PubMed] Free Access to Full Article Related Publications
Sclerosing epithelioid fibrosarcoma (SEF) is a rare soft tissue tumor exhibiting considerable morphologic overlap with low-grade fibromyxoid sarcoma (LGFMS). Moreover, both SEF and LGFMS show MUC4 expression by immunohistochemistry. While the majority of LGFMS cases are characterized by a FUS-CREB3L1 fusion, both FUS-CREB3L2 and EWSR1-CREB3L1 fusions were recently demonstrated in a small number of LGFMS and SEF/LGFMS hybrid tumors. In contrast, recent studies pointed out that SEF harbor frequent EWSR1 rearrangements, with only a minority of cases showing FUS-CREB3L2 fusions. In an effort to further characterize the molecular characteristics of pure SEF and hybrid SEF/LGFMS lesions, we undertook a clinicopathologic, immunohistochemical and genetic analysis of a series of 10 SEF and 8 hybrid SEF/LGFMS tumors. The mortality rate was similar between the two groups, 44% within the pure SEF group and 37% in the hybrid SEF/LGFMS with a mean overall follow-up of 66 months. All but one pure SEF and all hybrid SEF/LGFMS-tested cases showed MUC4 immunoreactivity. The majority (90%) of pure SEF cases showed EWSR1 gene rearrangements by fluorescence in situ hybridization with only one case exhibiting FUS rearrangement. Of the nine EWSR1 positive cases, six cases harbored CREB3L1 break-apart, two had CREB3L2 rearrangement (a previously unreported finding) and one lacked evidence of CREB3L1/2 abnormalities. In contrast, all hybrid SEF/LGFMS tumors exhibited FUS and CREB3L2 rearrangements. These results further demarcate a relative cytogenetic dichotomy between pure SEF, often characterized by EWSR1 rearrangements, and hybrid SEF/LGFMS, harboring FUS-CREB3L2 fusion; the latter group recapitulating the genotype of LGFMS.

Kurisaki-Arakawa A, Suehara Y, Arakawa A, et al.
Deeply located low-grade fibromyxoid sarcoma with FUS-CREB3L2 gene fusion in a 5-year-old boy with review of literature.
Diagn Pathol. 2014; 9:163 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue tumor typically affecting young to middle-aged adults. Despite its otherwise benign histologic appearance and indolent nature, it can have fully malignant behavior, and recurrence and metastasis may occur even decades later.
CASE HISTORY: We report a case of LGFMS in the left lower leg of a 5-year-old Japanese boy. A magnetic resonance imaging (MRI) uncovered a well-demarcated intra-gastrocnemial tumor measuring 27 × 20 mm with a slightly high intensity on T1WI and heterogeneously high intensity on T2WI. Histologically, the tumor was composed of bland spindle-shaped cells with a whorled growth pattern. The tumor stroma was variably hyalinized and fibromyxoid with arcades of curvilinear capillaries and arterioles with associated perivascular fibrosis. Although LGFMS is known to affect children under 18 years of age, it is extremely rare in infants and children under 5 years of age. Despite the young age, this patient was accurately diagnosed by the typical histology and the detection of a FUS-CREB3L2 gene fusion.
CONCLUSION: Although LGFMS in children tends to be located superficially, this case presented with an intramuscular tumor in the region of the gastrocnemius. To the best of our knowledge, this is the first case of deep LGFMS arising in a child younger than 5 years of age. The patient is still alive with no evidence of the disease 4 months after diagnosis.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_163.

McFadden DG, Dias-Santagata D, Sadow PM, et al.
Identification of oncogenic mutations and gene fusions in the follicular variant of papillary thyroid carcinoma.
J Clin Endocrinol Metab. 2014; 99(11):E2457-62 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) is increasingly common. Recent studies have suggested that FVPTC is heterogeneous and comprises multiple tumor types with distinct biological behaviors and underlying genetics.
OBJECTIVES: The purpose of this work was to identify the prevalence of mutations and gene fusions in known oncogenes in a panel representative of the common spectrum of FVPTC diagnosed at an academic medical center and correlate the clinical and pathological features obtained at the initial diagnosis with the tumor genotype.
MATERIALS AND METHODS: We performed SNaPshot genotyping on a panel of 129 FVPTCs of ≥1 cm for 90 point mutations or small deletions in known oncogenes and tumor suppressors and identified gene fusions using an anchored multiplex PCR assay targeting a panel of rearranged oncogenes.
RESULTS: We identified a mutation or gene fusion in 70% (89 of 127) of cases. Mutations targeting the RAS family of oncogenes were the most frequently observed class of alterations, present in 36% (46 of 127) of cases, followed by BRAF mutation, present in 30% (38 of 127). We also detected oncogenic rearrangements not previously associated with FVPTC, including TFG-ALK and CREB3L2-PPARγ. BRAF mutation was significantly associated with unencapsulated tumor status.
CONCLUSIONS: These data support the hypothesis that FVPTC is composed of distinct biological entities, with one class being identified by BRAF mutation and support the use of clinical genotyping assays that detect a diverse array of rearrangements involving ALK and PPARγ. Additional studies are necessary to identify genetic drivers in the 30% of FVPTCs with no known oncogenic alteration and to better predict behavior in tumors with known genotypes.

Rubinstein JC, Visa A, Zhang L, et al.
Primary low-grade fibromyxoid sarcoma of the kidney in a child with the alternative EWSR1-CREB3L1 gene fusion.
Pediatr Dev Pathol. 2014 Jul-Aug; 17(4):321-6 [PubMed] Related Publications
We present the case of a 6-year-old boy with a deceptively bland spindle cell renal neoplasm found to harbor the EWSR1-CREB3L1 gene fusion. This fusion has recently been described as a variant translocation in low-grade fibromyxoid sarcoma (LGFMS), a tumor more typically characterized by a recurrent t(7;16) chromosomal translocation, resulting in the fusion of FUS and CREB3L2 genes. LGFMS is an indolent tumor with late metastatic potential and a propensity for long-term disease recurrence. The tumor is rare in children, with only 33 published cases. In the pediatric population, it has not previously been reported arising in the kidney.

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.

Lau PP, Lui PC, Lau GT, et al.
EWSR1-CREB3L1 gene fusion: a novel alternative molecular aberration of low-grade fibromyxoid sarcoma.
Am J Surg Pathol. 2013; 37(5):734-8 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon sarcoma with a deceptively bland-looking morphology that disguises its malignant clinical behavior. It shows distinctive chromosomal translocations resulting in fusion of FUS with the CREB3L2 gene in most cases and CREB3L1 in rare cases. Thus molecular studies are particularly helpful in the diagnosis of this bland-looking sarcoma. We report 2 cases of LGFMS serendipitously found to harbor a novel alternative EWSR1-CREB3L1 gene fusion, as confirmed by DNA sequencing of reverse transcriptase-polymerase chain reaction products and fluorescence in situ hybridization. One patient was a child who presented with a subcutaneous nodule on the lower leg, and the other was a middle-aged woman who had a mass lesion over the proximal thigh. Morphologically, one case showed a spindle cell tumor with hyalinization and giant rosettes, whereas the other showed classical histology of LGFMS with focal metaplastic bone formation. Immunostaining for MUC4 showed extensive positive staining. Our findings therefore expand the spectrum of gene fusions that characterize LGFMS and suggest that the EWSR1 gene may substitute for the function of FUS in gene fusions of sarcoma.

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.

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.

Hisaoka M, Matsuyama A, Aoki T, et al.
Low-grade fibromyxoid sarcoma with prominent giant rosettes and heterotopic ossification.
Pathol Res Pract. 2012; 208(9):557-60 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma is a rare soft tissue sarcoma of fibroblastic differentiation characterized by a deceptively benign morphologic appearance with almost consistent MUC4 expression and recurrent chromosomal translocations, t(7;16)(q34;p11) and t(11;16)(p11;p11), resulting in the FUS-CREB3L2 and FUS-CREB3L1 fusion genes, respectively. A subset of the tumors show peculiar histologic features, designated as giant rosettes, and were formerly referred to as hyalinizing spindle cell tumor with giant rosettes. We herein report a case of low-grade fibromyxoid sarcoma showing the presence of numerous giant rosettes, with and without collagenous centers, distributed throughout the lesion and unusual rim-like heterotopic ossification. Such a case might present a diagnostic challenge. The diagnosis of the tumor was confirmed by positive immunoreactivity to MUC4 and the FUS-CREB3L2 fusion detected by molecular testing using formalin-fixed, paraffin-embedded tissue. This case, which has such unusual clinicopathologic features, would help to further expand our knowledge regarding the morphologic diversities of low-grade fibromyxoid sarcoma.

Lee AF, Yip S, Smith AC, et al.
Low-grade fibromyxoid sarcoma of the perineum with heterotopic ossification: case report and review of the literature.
Hum Pathol. 2011; 42(11):1804-9 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma was first described more than 20 years ago. Subsequently, it was discovered to carry the recurrent chromosomal translocation t(7;16)(q33;p11) encoding a FUS-CREB3L2 fusion oncoprotein. Molecular tests for this pathognomonic gene fusion can confirm the identity of histologic variants (such as hyalinizing spindle cell tumor with giant rosettes) and suggest that some cases of sclerosing epithelioid fibrosarcoma may represent a high-grade version of this entity. We present a case of an ossifying tumor of the perineum that required an open biopsy and fluorescent in situ hybridization testing for FUS and CREB3L2 for diagnosis as a variant of low-grade fibromyxoid sarcoma. Subsequent excision revealed characteristic areas with collagen rosettes as well as foci of heterotopic ossification. Significant ossification, which is well documented in entities such as synovial sarcoma, ossifying fibromyxoid tumor, and extraskeletal osteosarcoma, has not been reported previously in low-grade fibromyxoid sarcoma. This case demonstrates the value of having a distinctive confirmatory molecular pathology test for diagnosis and expands our knowledge of the histologic variants possible in low-grade fibromyxoid sarcoma.

Möller E, Hornick JL, Magnusson L, et al.
FUS-CREB3L2/L1-positive sarcomas show a specific gene expression profile with upregulation of CD24 and FOXL1.
Clin Cancer Res. 2011; 17(9):2646-56 [PubMed] Related Publications
PURPOSE: Low-grade fibromyxoid sarcoma (LGFMS) is typically characterized by the specific translocation t(7;16)(q33;p11) and the corresponding fusion gene FUS-CREB3L2. The present study aimed to extract LGFMS-specific, and putatively FUS-CREB3L2-dependent, gene expression patterns to learn more about the pathogenesis of this tumor.
EXPERIMENTAL DESIGN: We carried out single nucleotide polymorphism (SNP) and global gene expression array analyses, and/or immunohistochemical (IHC) analyses on 24 LGFMS tumor biopsies. Tumor types that are important differential diagnoses to LGFMS were included as comparison in the gene and protein expression analyses. In addition, cells that stably expressed FUS-CREB3L2 were analyzed with gene expression array and the influence of FUS-CREB3L2 on gene expression was investigated in vitro.
RESULTS: The SNP array analysis detected recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes. Gene expression analysis clearly distinguished LGFMS from morphologically similar tumors and MUC4 was identified as a potential diagnostic marker for LGFMS by gene expression and IHC analysis. FOXL1 was identified as the top upregulated gene in LGFMS and CD24 was upregulated in both LGFMS tumors and FUS-CREB3L2 expressing cells. FUS-CREB3L2 was capable of activating transcription from CD24 regulatory sequences in luciferase assays, suggesting an important role for the upregulation of this gene in LGFMS.
CONCLUSIONS: The gene expression profile of LGFMS is distinct from that of soft tissue tumors with similar morphology. The data could be used to identify a potential diagnostic marker for LGFMS and to identify possible FUS-CREB3L2 regulated genes.

Doyle LA, Möller E, Dal Cin P, et al.
MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma.
Am J Surg Pathol. 2011; 35(5):733-41 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) is a distinctive fibroblastic neoplasm that is characterized by alternating collagenous and myxoid areas, deceptively bland spindle cell morphology, a whorling architecture, and a t(7;16) translocation involving FUS and CREB3L2. Owing to variable morphology and a lack of discriminatory markers, LGFMS can be difficult to distinguish from benign mesenchymal tumors and other low-grade sarcomas. Gene expression profiling has identified differential upregulation of the mucin 4 (MUC4) gene in LGFMS compared with histologically similar tumors. MUC4 is a transmembrane glycoprotein that functions in cell growth signaling pathways; aberrant MUC4 expression has been reported in various carcinomas. We investigated MUC4 protein expression by immunohistochemistry in LGFMS and in other soft tissue tumors to determine the potential diagnostic use of this novel marker. Whole-tissue sections of 309 tumors were evaluated: 49 LGFMSs (all with FUS gene rearrangement confirmed by fluorescence in situ hybridization), 40 soft tissue perineuriomas, 40 myxofibrosarcomas, 20 cellular myxomas, 20 solitary fibrous tumors, 20 low-grade malignant peripheral nerve sheath tumors, 20 cases of desmoid fibromatosis, 20 neurofibromas, 20 schwannomas, 20 monophasic synovial sarcomas, 20 cases of dermatofibrosarcoma protuberans, 10 myxoid liposarcomas, and 10 extraskeletal myxoid chondrosarcomas. The LGFMS cases included 7 with marked hypercellularity, 4 with prominent hemangiopericytoma-like vessels, 3 with giant collagen rosettes, 3 with epithelioid morphology, 2 with focal nuclear pleomorphism, and 2 with areas of sclerosing epithelioid fibrosarcoma. All 49 LGFMS cases (100%) showed cytoplasmic staining for MUC4, which was usually diffuse and intense. All the other tumor types were negative for MUC4, apart from 6 (30%) monophasic synovial sarcomas. In conclusion, MUC4 is a highly sensitive and quite specific immunohistochemical marker for LGFMS, and can be helpful to distinguish this tumor type from histologic mimics.

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.

Dhillon MS, Mootha AK, Kumar V, et al.
Low-grade fibromyxoid sarcoma of the talus: a case report.
J Foot Ankle Surg. 2010 Jul-Aug; 49(4):400.e5-8 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma is a rare tumor, which most commonly arises from the deep soft tissues of the lower extremities in young men. Diagnosis of this tumor can be difficult because of its deceptively benign histopathologic appearance. Specifically, the lesion is characterized by alternating fibrous and myxoid areas with variable cellularity and a whorled growth pattern. Like many soft tissue tumors, low-grade fibromyxoid sarcoma is also characterized by strong immunoreactivity to the human proto-oncogene BCL-2. Cytogenetically, the lesion has also been associated with the t (7,16) (q33;p11) translocation, with the characteristic resultant FUS and CREB3L2 fusion gene. In this report, we describe the rare case of a low-grade fibromyxoid sarcoma that appeared to develop as a primary malignancy in the neck of the talus of a young man who presented with recurrent ankle pain after a previous surgery for a cystic lesion at the same site.

Rekhi B, Folpe AL, Deshmukh M, Jambhekar NA
Sclerosing epithelioid fibrosarcoma - a report of two cases with cytogenetic analysis of FUS gene rearrangement by FISH technique.
Pathol Oncol Res. 2011; 17(1):145-8 [PubMed] Related Publications
Sclerosing epithelioid fibrosarcoma (SEF) is a rare soft tissue sarcoma. Recently, a link has been suggested between SEF and low-grade fibromyxoid sarcoma (LGFMS) on the basis of the finding of the characteristic translocation t(7;16) (FUS-CREB3L2) of LGFMS in a small number of studied cases of SEF. The frequency of this translocation in SEF is still unknown. We present 2 cases of SEF with cytogenetic analysis for FUS rearrangement. The tumors occurred in 12 and 58 year old patients, respectively and consisted of a well to partially circumscribed, non-encapsulated mass, comprising monomorphic, polygonal cells arranged in aggregates, cords and single file arrays in a variably sclerotic stroma. The cells exhibited minimal nuclear atypia with moderate amount of clear to eosinophilic cytoplasm and rare mitotic figures. One case also showed bland spindle cell areas with myxoid change, as seen in LGFMS. By immunohistochemistry (IHC), the tumor cells were diffusely positive for vimentin, focally for S-100 in 1 case and negative for cytokeratin (CK), epithelial membrane antigen (EMA), HMB-45, desmin, smooth muscle actin (SMA), H-caldesmon, Myo D-1, CD34 and CD 168. By fluorescent in-situ hybridization (FISH) technique, the case with mixed SEF and LGFMS histology was positive for FUS rearrangement. Our study reinforces the previously reported relationship between SEF and LGFMS, and suggests that SEF may represent a variant of LGFMS in at least some cases, rather than an entirely distinct fibrosarcoma variant.

Sheng Z, Li L, Zhu LJ, et al.
A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications.
Nat Med. 2010; 16(6):671-7 [PubMed] Free Access to Full Article Related Publications
Activating transcription factor-5 (ATF5) is highly expressed in malignant glioma and has a key role in promoting cell survival. Here we perform a genome-wide RNAi screen to identify transcriptional regulators of ATF5. Our results reveal an essential survival pathway in malignant glioma, whereby activation of a RAS-mitogen-activated protein kinase or phosphoinositide-3-kinase signaling cascade leads to induction of the transcription factor cAMP response element-binding protein-3-like-2 (CREB3L2), which directly activates ATF5 expression. ATF5, in turn, promotes survival by stimulating transcription of myeloid cell leukemia sequence-1 (MCL1), an antiapoptotic B cell leukemia-2 family member. Analysis of human malignant glioma samples indicates that ATF5 expression inversely correlates with disease prognosis. The RAF kinase inhibitor sorafenib suppresses ATF5 expression in glioma stem cells and inhibits malignant glioma growth in cell culture and mouse models. Our results demonstrate that ATF5 is essential in malignant glioma genesis and reveal that the ATF5-mediated survival pathway described here provides potential therapeutic targets for treatment of malignant glioma.

Bartuma H, Möller E, Collin A, et al.
Fusion of the FUS and CREB3L2 genes in a supernumerary ring chromosome in low-grade fibromyxoid sarcoma.
Cancer Genet Cytogenet. 2010; 199(2):143-6 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) is a rare, low-grade malignant soft tissue tumor that is often mistaken for either benign or more malignant tumor types. Commonly, this tumor affects young adults and typically arises in the deep proximal extremities or trunk with frequent recurrences and can metastasize to the lungs many years later. Most cases have a recurrent balanced translocation involving chromosomes 7 and 16, t(7;16)(q32-34;p11), which leads to the fusion of the FUS and CREB3L2 genes. However, supernumerary ring chromosomes have been identified in a subset of FUS/CREB3L2-positive LGFMS, but it has not yet been formally demonstrated that such ring chromosomes harbor the FUS/CREB3L2 fusion gene. Here, we report the genetic findings of a supernumerary ring chromosome from an LGFMS from a 77-year-old man. Chromosome banding analysis revealed a supernumerary ring chromosome, and further studies with fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the ring contained material from chromosomes 7 and 16, that the FUS gene was present in two rearranged copies, and that it expressed the FUS/CREB3L2 fusion gene. Moreover, an assessment of previously reported cases showed that tumors with ring chromosomes relapsed more often than tumors with a balanced t(7;16), suggesting that ring formation in LGFMS is correlated with tumor progression.

Liao KS, Huang WT, Yang SF, et al.
Intramuscular low-grade fibromyxoid sarcoma: a case report.
Kaohsiung J Med Sci. 2009; 25(8):448-54 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) is a rare neoplasm that commonly arises in the deep soft tissues of the lower extremities, particularly in the thigh. LGFMS occurs preferentially in young male adults. The microscopic appearance of LGFMS exhibits bland fibroblastic spindle cells with a whorled or linear arrangement in fibrous and myxoid areas. Although LGFMS has a deceptively benign histologic appearance, local recurrence and late metastases have frequently been reported. Diagnosis of LGFMS is still difficult because of its characteristic bland-looking histologic features that can be confused with other benign or low-grade fibromyxoid lesions. Although immunohistochemical staining can offer an overview of the differential diagnosis of myxoid tumors of soft tissue, it is sometimes limited for diagnosis of LGFMS. However, recent cytogenetic and molecular analyses have provided significant improvements in the diagnosis of LGFMS. Such analyses have demonstrated that most cases of LGFMS have a characteristic t(7,16)(q33;p11) translocation, resulting in the FUS-CREB3L2 fusion gene. We report a 29-year-old female who presented with a LGFMS located in the soleus muscle of her left lower leg. Preoperative imaging suggested the possibility of an intramuscular histiocytoma of the left soleus muscle. In conclusion, diagnosis of LGFMS can be challenging in routine practice in surgical pathology because of its bland-looking features. The immunohistochemical and ultrastructural findings were consistent with the fibroblastic properties of LGFMS. Cytogenetic and/or molecular genetic analyses can be used as ancillary diagnostic tools for LGFMS.

Lui WO, Zeng L, Rehrmann V, et al.
CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis.
Cancer Res. 2008; 68(17):7156-64 [PubMed] Related Publications
The discovery of gene fusion mutations, particularly in leukemia, has consistently identified new cancer pathways and led to molecular diagnostic assays and molecular-targeted chemotherapies for cancer patients. Here, we report our discovery of a novel CREB3L2-PPARgamma fusion mutation in thyroid carcinoma with t(3;7)(p25;q34), showing that a family of somatic PPARgamma fusion mutations exist in thyroid cancer. The CREB3L2-PPARgamma fusion encodes a CREB3L2-PPARgamma fusion protein that is composed of the transactivation domain of CREB3L2 and all functional domains of PPARgamma1. CREB3L2-PPARgamma was detected in <3% of thyroid follicular carcinomas. Engineered overexpression of CREB3L2-PPARgamma induced proliferation by 40% to 45% in primary human thyroid cells, consistent with a dominant oncogenic mechanism. Wild-type CREB3L2 was expressed in the thyroid as a bZIP transcription factor with a transmembrane domain that has flanking S1P and S2P proteolytic cleavage sites. Native CREB3L2 was cleaved to nuclear CREB3L2 by regulated intramembrane proteolysis in normal thyroid cells that expressed the S1P and S2P proteases. Nuclear CREB3L2 stimulated transcription 8-fold from the EVX1 cyclic AMP (cAMP) response element in the absence of cAMP, whereas CREB3L2-PPARgamma inhibited transcription 6-fold from EVX1 in the same experiments. CREB3L2-PPARgamma also inhibited 4-fold the expression of thyroglobulin, a native cAMP-responsive gene, in primary thyroid cells treated with thyroid-stimulating hormone. Our findings identify a novel CREB3L2-PPARgamma gene fusion mutation in thyroid carcinoma and reveal a thyroid signaling pathway that is regulated by intramembrane proteolysis and disrupted in cancer.

Matsuyama A, Hisaoka M, Shimajiri S, Hashimoto H
DNA-based polymerase chain reaction for detecting FUS-CREB3L2 in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens.
Diagn Mol Pathol. 2008; 17(4):237-40 [PubMed] Related Publications
Detection of the tumor-specific fusion gene, FUS-CREB3L2, is useful in the diagnosis of low-grade fibromyxoid sarcoma (LGFMS), especially by reverse transcription (RT)-polymerase chain reaction (PCR) using formalin-fixed, paraffin-embedded (FFPE) tumor tissues. Because FUS and CREB3L2 gene segments with their break points within exons are fused without interposed introns in many LGFMSs, DNA-based PCR may also be applicable to detect the FUS-CREB3L2 fusion gene using FFPE specimens. In this study, DNA and RNA were extracted from FFPE specimens of 16 and 19 LGFMSs, respectively, and PCR and RT-PCR were performed using primers that specifically amplify most of the junctional regions of the FUS-CREB3L2 fusion gene. RT-PCR analysis revealed FUS-CREB3L2 fusion transcripts in 16 of the 19 (84%) LGFMSs. In 14 informative examples, including 11 with detectable fusion transcripts by RT-PCR, DNA-based PCR amplified the FUS-CREB3L2 fusion gene in 9 (64%) examples. Nucleotide sequence analysis confirmed that PCR products were identical to the respective RT-PCR products in 8 cases. Although the sensitivity was not as high as RT-PCR, DNA-based PCR can be used as an alternative molecular approach for detecting the FUS-CREB3L2 fusion gene.

Downs-Kelly E, Goldblum JR, Patel RM, et al.
The utility of fluorescence in situ hybridization (FISH) in the diagnosis of myxoid soft tissue neoplasms.
Am J Surg Pathol. 2008; 32(1):8-13 [PubMed] Related Publications
Diagnosing myxoid soft tissue neoplasms can be challenging because of overlapping histologic features. Distinct chromosomal translocations have been identified in several myxoid sarcomas, including t(12;16)(q13;p11) FUS-DDIT3 in myxoid liposarcoma, t(7;16)(q34;p11) FUS-CREB3L2 in low-grade fibromyxoid sarcoma, and t(9;22)(q31;q12) EWSR1-NR4A3 in extraskeletal myxoid chondrosarcoma. These recurrent chromosomal alterations are attractive targets for diagnostic studies. To that end, dual-color, break-apart fluorescence in situ hybridization (FISH) probes spanning the genomic regions of EWSR1 (22q12), DDIT3 (12q13), and FUS (16p11) (Vysis, Downer's Grove, IL) were evaluated in formalin-fixed, paraffin-embedded tissues from myxoid neoplasms, including intramuscular myxoma (n=10), myxoid liposarcoma (n=18), low-grade fibromyxoid sarcoma (n=10), extraskeletal myxoid chondrosarcoma (n=13), and myxofibrosarcoma (n=8). Of the myxoid liposarcomas, 18/18 cases had a rearrangement of the DDIT3 gene, with 17/18 (94.4%) showing both DDIT3 and FUS gene rearrangements. A FUS gene rearrangement was identified in 7/10 (70%) of low-grade fibromyxoid sarcomas, with no changes involving EWSR1 or DDIT3. An EWSR1 translocation was seen in 6/13 (46.2%) of extraskeletal myxoid chondrosarcomas, without changes in DDIT3 or FUS genes. The remaining neoplasms studied showed no rearrangements involving DDIT3, FUS, or EWSR1 genes. In conclusion, interphase FISH using DDIT3 and FUS probes identifies the characteristic translocation in myxoid liposarcoma. FUS and EWSR1 probes are useful in confirming the diagnosis of low-grade fibromyxoid sarcoma and extraskeletal myxoid chondrosarcoma, respectively. The specificity of the probes is documented as none of the non-translocation-associated myxoid tumors showed genomic abnormalities with the probes tested. FISH is capable of providing specific ancillary information useful in this often difficult differential diagnosis.

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