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

Written2014-12Charles Walther, Fredrik Mertens
Department of Pathology, University, Regional Laboratories, Skne University Hospital, 221 85 Lund, Charles.walther@med.lu.se (CW; Department of Clinical Genetics, University, Regional Laboratories, Skne University Hospital, Lund University, 221 85 Lund, Fredrik.Mertens@med.lu.se (FM)Sweden

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Abstract

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.

Identity

Atlas_Id 6473
Other namesEpitheloid sarcoma-like hemangioendothelioma

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

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).

Cytogenetics

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

Genes involved and Proteins

Note SERPINE1 and FOSB
Gene Name SERPINE1
Location 7q22.1; chr7:100,770,370-100,782,547
Dna / Rna 12,178 nt
Protein 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
Location 19q13.32; chr19:45,971,253-45,978,437
Dna / Rna 7,185 nt
Protein 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

Hybrid Gene
 
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).
Fusion Protein
Oncogenesis The role of SERPINE1 in the SERPINE1-FOSB chimera is probably to provide a promoter allowing strong expression of FOSB.
  

Bibliography

Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin
Declerck PJ, Gils A
Semin Thromb Hemost 2013 Jun;39(4):356-64
PMID 23504606
 
Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior
Hornick JL, Fletcher CD
Am J Surg Pathol 2011 Feb;35(2):190-201
PMID 21263239
 
The Fos family of transcription factors and their role in tumourigenesis
Milde-Langosch K
Eur J Cancer 2005 Nov;41(16):2449-61
PMID 16199154
 
Translocation t(7;19)(q22;q13) recurrent chromosome aberration in pseudomyogenic hemangioendothelioma? Cancer Genet
Trombetta D, Magnusson L, von Steyern FV, Hornick JL, Fletcher CD, Mertens F
2011 Apr;204(4):211-5 doi: 10
PMID 21536240
 
A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma
Walther C, Tayebwa J, Lilljebjörn H, Magnusson L, Nilsson J, von Steyern FV, Øra I, Domanski HA, Fioretos T, Nord KH, Fletcher CD, Mertens F
J Pathol 2014 Apr;232(5):534-40
PMID 24374978
 

Citation

This paper should be referenced as such :
Walther C, Mertens F
Pseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) SERPINE1/FOS
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Tumors/PHEt0719q22q13ID6473.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(7;19)(q22;q13) SERPINE1/FOSB

External links

Mitelman database t(7;19)(q22;q13) SERPINE1/FOSB [Case List]    t(7;19)(q22;q13) SERPINE1/FOSB [Association List] Mitelman database (CGAP - NCBI)
arrayMap arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseSERPINE1/FOSB[MCList]    SERPINE1 (7q22.1) FOSB (19q13.32)   
Mitelman databaseSERPINE1/FOSB[MCList]    SERPINE1 (7q22.1) FOSB (19q13.32)   t(7;19)(q22;q13)
 
Disease databasePseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) SERPINE1/FOSB
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed


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indexed on : Wed Apr 12 11:24:02 CEST 2017


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