Pseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) SERPINE1/FOSB

2014-12-01   Charles Walther  , Fredrik Mertens  

1.Department of Pathology, University, Regional Laboratories, Skne University Hospital, 221 85 Lund, [email protected] (CW; Department of Clinical Genetics, University, Regional Laboratories, Skne University Hospital, Lund University, 221 85 Lund, [email protected] (FM)Sweden

Abstract

Pseudomyogenic hemangioendothelioma (PHE) is an intermediate malignant vascular tumor primarily affecting soft tissues in children and young adults. The molecular basis of this neoplasm is unknown. Chromosome banding analysis, fluorescence in situ hybridization (FISH), mRNA sequencing, RT-PCR, and quantitative real-time PCR have shown that PHEs are characterized by a balanced translocation t(7;19)(q22;q13), resulting in the fusion of the SERPINE1 and FOSB genes. The role of SERPINE1, which is highly expressed in vascular cells, in this gene fusion is probably to provide a strong promoter for FOSB. FOSB encodes a transcription factor belonging to the FOS family of proteins, which together with members of the JUN family of transcription factors are major components of the Activating Protein 1 (AP-1) complex.

Clinics and Pathology

Note

Newly recognised entity. Rare. Exact incidence not known.

Etiology

Not known.

Epidemiology

Often young adults. Predominantly male (4.6:1)

Clinics

Two thirds of the lesions seen in limbs followed by trunk and head and neck. Size 0.3-5.5 cm. Often multifocal and ill circumscribed. Situated subcutanously but often in different tissue planes, including bone. Painful nodules in 50% of the cases. Locally aggressive and often recurring but rarely distant metastases. (Hornick et al., 2011)

Pathology

Spindle cells in fascicles and sheets. Vesicular nuclei. Distinct eosinophilic cytoplasm. Cells often show a rhabdomyoblast-like appearance.

Treatment

Surgical resection

Cytogenetics

Cytogenetics morphological

a recurrent translocation t(7;19)(q22;q13) has been seen.
Atlas Image
Interphase FISH with BAC probes showing normal red (SERPINE1) and green (FOSB) signals and yellow fusion (SERPINE1-FOSB) signal.

Genetics

Note

PHE consistently displays a SERPINE1-FOSB fusion gene, resulting from a translocation between chromosomes 7 and 19, presumably constituting the essential driver mutation in this neoplasm (Trombetta et al., 2011).

Genes Involved and Proteins

Note

SERPINE1 and FOSB

Gene name

SERPINE1 (serpin family E member 1)

Location

7q22.1

Dna rna description

12,178 nt

Protein description

SERPINE1 (aka PAI-1, plasminogen activator inhibitor type 1) encodes a protein that is a member of the serine protease inhibitor family, and that inhibits tissue- and urokinase-type plasminogen activators. These activators convert plasminogen to plasmin, which in turn mediates fibrinolysis and proteolytic degradation of extracellular matrix. It is highly expressed in many tumors, being implicated in invasion, angiogenesis and metastasis (Declerck et al., 2013).

Gene name

FOSB (FosB proto-oncogene, AP-1 transcription factor subunit)

Location

19q13.32

Dna rna description

7,185 nt

Protein description

Member of FOS family of genes, which code for leucine zipper proteins that act as transcription factors. FOSB consists of 338 amino acids (aa), with a central basic leucine-zipper region and a carboxy-terminal transactivation domain (TAD) (Milde-Langosh, 2005).

Result of the chromosomal anomaly

Atlas Image
Chromatogram showing the fusion junction in a case of PHE. Sixty-one nucleotides from intron 1 of SERPINE1 were inserted at the fusion junction (blue double arrow). The translation start codon in FOSB is indicated (black arrow).

Transcript

RT-PCR and subsequent sequencing of amplified products from two cases identified an in-frame SERPINE-/FOSB fusion transcripts in both cases. In both tumors the breakpoints in SERPINE1 were located in the non-coding exon 1. The breakpoint in FOSB was located in the beginning of exon 2 in one case and in the non-coding exon 1 in the other. Both cases showed small insertions (61 bp in Case 1, 59 bp in Case 2) of material from intron 1 of SERPINE1 at the fusion junction (Walther et al., 2014).

Oncogenesis

The role of SERPINE1 in the SERPINE1-FOSB chimera is probably to provide a promoter allowing strong expression of FOSB.

Highly cited references

Pubmed IDYearTitleCitations
383378582024Molecularly Confirmed Pseudomyogenic Hemangioendothelioma with Unusual EGFL7::FOSB Fusion in the Head and Neck Region of an Older Patient.43
333771242020Vascular Tumor Recapitulated in Endothelial Cells from hiPSCs Engineered to Express the SERPINE1-FOSB Translocation.40
302562582018Expanding the Spectrum of Genetic Alterations in Pseudomyogenic Hemangioendothelioma With Recurrent Novel ACTB-FOSB Gene Fusions.39
250439492014ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features.33
312431102019Fusion of the Genes WWTR1 and FOSB in Pseudomyogenic Hemangioendothelioma.14
243749782014A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma.0
345809032021A novel SERPINE1-FOSB fusion gene in pseudomyogenic hemangioendothelioma results in activation of intact FOSB and the PI3K-AKT-mTOR signaling pathway and responsiveness to sirolimus.0
286224282017Cutaneous pseudomyogenic (epithelioid sarcoma-like) haemangioendothelioma FOSB immunohistochemistry demonstrating the SERPINE1-FOSB fusion gene.0
295110302018Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma.0
257496272015Penile pseudomyogenic hemangioendothelioma/epithelioid sarcoma-like hemangioendothelioma with a novel pattern of SERPINE1-FOSB fusion detected by RT-PCR--report of a case.0
282745122017Practical use and utility of fluorescence in situ hybridization in the pathological diagnosis of soft tissue and bone tumors.0
280096082017FOSB is a Useful Diagnostic Marker for Pseudomyogenic Hemangioendothelioma.0

Article Bibliography

Pubmed IDLast YearTitleAuthors
235046062013Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin.Declerck PJ et al
212632392011Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior.Hornick JL et al
161991542005The Fos family of transcription factors and their role in tumourigenesis.Milde-Langosch K et al
215362402011Translocation t(7;19)(q22;q13)−a recurrent chromosome aberration in pseudomyogenic hemangioendothelioma?Trombetta D et al
243749782014A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma.Walther C et al

Citation

Charles Walther ; Fredrik Mertens

Pseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) SERPINE1/FOSB

Atlas Genet Cytogenet Oncol Haematol. 2014-12-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/6473/pseudomyogenic-hemangioendothelioma-t(7