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Soft tissue chondroma with t(3;12)(q27;q15) HMGA2/LPP

Identity

ICD-Topo C470-C476,C478-C479,C490-C496,C498-C499
Phylum Soft Tissue Tumors:ChondroOsseous tumors:Soft tissue chondroma:t(3;12)(q27;q15)

Clinics and Pathology

Disease Soft tissue chondroma with t(3;12)(q27;q15).
Note Only one case has been described to date.
Embryonic origin The embryonic origin is unknown, but the tumor cells presumably derive from the mesoderm.
Etiology Unknown.
Epidemiology The only case of soft tissue chondroma with t(3;12)(q27;q15) described to date was a tumor resected from a 62-year-old man.
Clinics The tumor presented as a solitary mass (8 x 6 x 8 cm) in the elbow region (fossa cubiti).
Pathology The tumor displayed a multilobulated growth pattern and was composed of mature adult hyaline cartilage with peripheral areas of myxofibromatous/lipomatous tissue and metaplastic bone tissue.
Treatment The tumor was removed with marginal excision.

Cytogenetics

Cytogenetics
Morphological
The t(3;12)(q27;q15) has so far been described in one case of soft tissue chondroma. The same translocation has been identified as a recurrent chromosomal aberration in ordinary lipoma and pulmonary chondroid hamartoma.
Cytogenetics Molecular Metaphase FISH mapping using cosmid probes specific for exons 1-2 (142H1) and exons 4-5 (27E12) of HMGA2 revealed that the breakpoint in chromosome band 12q15 was located within the large intron 3 of HMGA2.

Genes involved and Proteins

Gene Name HMGA2 (high mobility group AT-hook 2).
Location 12q15.
Dna / Rna The gene consists of 5 exons that span approximately 160 kb of genomic DNA in the centromere-to-telomere orientation. The first three exons are separated from the last two exons by a particularly large intron (about 112 kb). The corresponding transcript is approximately 4,1 kb (referred to as wildtype or isoform a transcript of HMGA2). The translation initiation codon ATG is located in exon 1 and the stop codon in exon 5.
Several alternative splice products of HMGA2 have been reported (referred to as isoforms b, c, d, e and f transcripts of HMGA2, respectively).
Protein The open reading frame encodes a 108 amino acid protein with an estimated molecular weight of approximately 12 kDa.
The first 3 exons each encode a DNA-binding domain. Exons 4 and 5 encode a spacer domain and an acidic domain, respectively. It has been suggested that the 3'-UTR acts as a negative regulator of the expression of HMGA2.
The HMGA2 protein is a member of the HMGA (high mobility group A) family of proteins and is believed to affect transcription as architectural elements by bending the DNA and by interacting with a large number of proteins, mainly transcription factors. Reported specific targets of the HMGA2 protein are the pRB protein, as well as the promoter regions of the DNA-repair gene ERCC1 and the cyclin A gene.

Gene Name LPP (LIM domain containing preferred translocation partner in lipoma).
Location 3q27-28.
Dna / Rna The gene consists of 11 exons and spans approximately 667 kb of genomic DNA in the centromere-to-telomere orientation. The corresponding transcript is approximately 7,3 kb. The translation initiation codon is located in exon 3 and the stop codon in exon 11.
Protein The open reading frame encodes a 612 amino acid protein.
The protein is composed of a proline rich N-terminal and 3 LIM domains in its C-terminal. Exons 3-7 encode the proline-rich domain. Exon 8 encodes the LIM1 domain and exon 9 encodes the LIM2 domain. Exon 10 and parts of exon 11 encode the LIM3 domain.
The LPP protein is a member of the zyxin family (also referred to as group 3) of LIM domain proteins. The LIM-domain encodes a double zink finger motif involved in protein-protein interactions. Functionally the LPP protein interacts with cytoplasmic proteins involved in focal adhesion and cell-to-cell contact, but it does also shuttle between the cytoplasm and the nucleus and has therefore been attributed a role in signal transduction processes. It has recently been shown that the LIM domains of LPP function as a transcriptional coactivator of the transcription factor PEA3/ ETV4.

Result of the chromosomal anomaly

Hybrid Gene
Note Only one case has been described to date.
Description The structure of the hybrid gene has not been investigated at the genomic level in soft tissue chondroma with t(3;12)(q27;q15).
Transcript The detected HMGA2-LPP fusion transcript was composed of the first 3 exons of HMGA2 and exons 9-11 of LPP. Identical fusion transcripts have previously been detected in ordinary lipoma and pulmonary chondroid hamartoma. The findings of identical fusion transcripts in different tumor types have strengthened the notion that it is not the formation of the HMGA2-LPP fusion per se that directs tumor cell differentiation.
Detection Several detailed protocols for the detection of the HMGA2-LPP fusion transcript have been published.
Fusion Protein
Note The HMGA2-LPP fusion protein has not been functionally studied in soft tissue chondroma with t(3;12)(q27;q15).
Description The HMGA2-LPP fusion protein is composed of the DNA-binding domains of HMGA2 and the LIM2 and LIM3 domains of LPP.
Expression Localisation In transfection assays of 3T3-L1 cells it has been shown that the HMGA2-LPP fusion protein is located in the nucleus.
Oncogenesis It has been suggested that the abnormal tumor cell proliferation is caused by a disruption in the balance of co-expression between the wildtype HMGA2 transcript and its splice variants.
  

Translocations implicated (Data extracted from papers in the Atlas)

 t(3;12)(q27;q15) HMGA2/LPP

External links

Mitelman database
t(3;12)(q27;q15) - Mitelman database (CGAP - NCBI)
COSMICHisto = - Site = soft_tissue (COSMIC)
arrayMapTopo ( C47,C49) arrayMap (Zurich)

Bibliography

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Contributor(s)

Written10-2006Anna Collin
Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden

Citation

This paper should be referenced as such :
Collin, A
Soft tissue chondroma with t(3;12)(q27;q15)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1):54-56.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Tumors/Chondromat0312ID5428.html

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indexed on : Tue Sep 23 17:33:36 CEST 2014


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