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Soft Tissues: Ordinary lipoma with t(1;12)(p32;q14) HMGA2/PPAP2B

Written2014-12Laurence Bianchini
Institute for Research on Cancer, Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, University of Nice-Sophia Antipolis, Nice, France / laurence.bianchini@unice.fr

(Note : for Links provided by Atlas : click)

Abstract

Abstract Review on lipoma with t(1;12)(p32;q14) HMGA2/PPAP2B, with data on clinics, and the genes involved.

Identity

Atlas_Id 6602
Phylum Soft Tissues::Lipoma

Classification

    Benign lipomatous neoplasm

Clinics and Pathology

Disease Ordinary lipoma
Note First description of the involvement of PPAP2B in a chromosomal translocation
Epidemiology Ordinary lipomas are the most frequent mesenchymal human tumors
Clinics The tumor presented as a solitary mass (5.5 x 4.5 x 2.5 cm) located in the right chest wall.

Cytogenetics

Cytogenetics
Morphological
The t(1;12)(p32;q14) translocation had already been described in lipomas (Mitelman et al., 2014) in a limited number of cases but had never been explored at the molecular level until our report (Bianchini et al., 2013).
Cytogenetics Molecular Rearrangements of HMGA2 and PPAP2B were detected by metaphase FISH mapping using the dual-color break-apart FISH probes set RP11-30I11 (HMGA2 5' region) and RP11-118B13 (HMGA2 3' region) and the dual-color break-apart FISH probes set RP11-485A11 (telomeric to the PPAP2B 3' UTR region) and RP11-20I22 (flanking the PPAP2B 5' UTR region) respectively.

Genes involved and Proteins

Gene NameHMGA2 (high mobility group AT-hook 2)
Location 12q14.3
Dna / Rna HMGA2 (formerly HMGI-C) is a member of the HMGA (high mobility group A) family. The gene is composed of 5 exons and spans approximately 160 kb. Exons 3 and 4 are separated by a very large intron (more than 140 kb) where breakpoints have been reported to occur preferentially in lipoma cases harbouring HMGA2 rearrangements (Ashar et al., 1995).
Protein The protein is composed of 108 amino acid residues. It contains three DNA-binding domains (AT-hooks) -encoded by the three first exons- and an acidic carboxy-terminal region -encoded by the fifth exon- which may be involved in protein-protein interactions. HMGA2 is an architectural transcription factor which does not have a transcription activity per se but contributes to transcriptional regulation by remodeling chromatin architecture. Chromosomal rearrangements involving HMGA2 have been described in various benign tumors mostly of mesenchymal origin including lipomas (Ashar et al., 1995; Schoenmakers et al., 1995).

Gene NamePLPP3 (phospholipid phosphatase 3)
Location 1p32.2
Dna / Rna PPAP2B is a member of the phosphatidic acid phosphatase (PAP) gene family. The PPAP2B gene contains 6 exons and spans more than 84 kb.
Protein The protein (311 amino acids and 35 kDa) encoded by the PPAP2B gene is LPP3 a member of the lipid phosphate phosphatase (LPP) family. LPPs are enzymes that catalyze the dephosphorylation of lipid phosphates including phosphatidate and lysophosphatidic acid. LPP3 is a glycoprotein containing 6 transmembrane regions and three catalytic domains. LPP3 has been reported to be involved in vasculogenesis (Escalante-Alcalde et al., 2003), neuron differentiation and neurite outgrowth (Sanchez-Sanchez et al., 2012). Only a limited number of studies have reported the potential involvement of LPP3 in tumorigenesis (Tanyi et al., 2003; Zhou et al., 2010; Chatterjee et al., 2011).

Result of the chromosomal anomaly

Hybrid Gene
Description The t(1;12)(p32;q14) in this lipoma case results in a chimeric HMGA2-PPAP2B transcript fusioning HMGA2 3' untranslated region (UTR) with PPAP2B exon 6. The breakpoint in HMGA2 3' UTR is located downstream of the first let-7 microRNA binding site.
Detection The chromosomal breakpoints of the t(1;12)(p32;q14) were first defined using a FISH-based positional cloning strategy followed by RT-PCR to detect potential fusion transcripts. RT-PCR products have been finally sequenced using traditional Sanger sequencing.
Fusion Protein
Note Although more than 40 chromosome bands have been described in rearrangements involving the 12q13-15 region in lipomas (Bartuma et al., 2007), only five genes have been identified as fusion partners of HMGA2 before PPAP2B: LPP (3q28), CXCR7 (2q37), EBF1 (5q33), LHFP (13q12) and NFIB (9p22) (Petit et al., 1996; Petit et al., 1999; Broberg et al., 2002; Nilsson et al., 2005; Nilsson et al., 2006; Hatano et al., 2008; Italiano et al., 2008).
Description The translocation preserves the full coding region of HMGA2 so the HMGA2-PPAP2B fusion transcript is predicted to encode a full length HMGA2 protein.
Oncogenesis The 3' UTR of HMGA2 contains multiple binding sites for the let-7 family. Targeted mutations of these binding sites or functional inactivation of let-7 result in upregulation of HMGA2 (Lee and Dutta, 2007; Mayr et al., 2007). We have observed that the t(1;12)(p32;q14) translocation results in a strong HMGA2 overexpression both at the mRNA and protein levels. Our results therefore confirm the hypothesis that HMGA2 overexpression can be induced by removal of the let-7 binding sites in HMGA2 3' UTR. Additional studies must be performed to clarify whether PPAP2B plays a role in the tumorigenesis of t(1;12) lipoma.
  

Bibliography

Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (2014)
Mitelman F, Johansson B and Mertens F (Eds).
http://cgap.nci.nih.gov/Chromosomes/Mitelman
 
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Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype
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Identification of PPAP2B as a novel recurrent translocation partner gene of HMGA2 in lipomas
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Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15
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The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning
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NFIB rearrangement in superficial, retroperitoneal, and colonic lipomas with aberrations involving chromosome band 9p22
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The tumor suppressor microRNA let-7 represses the HMGA2 oncogene
Lee YS, Dutta A
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Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation
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Truncation and fusion of HMGA2 in lipomas with rearrangements of 5q32-->q33 and 12q14-->q15
Nilsson M, Mertens F, Höglund M, Mandahl N, Panagopoulos I
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Fusion of the HMGA2 and NFIB genes in lipoma
Nilsson M, Panagopoulos I, Mertens F, Mandahl N
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LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family
Petit MM, Mols R, Schoenmakers EF, Mandahl N, Van de Ven WJ
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LHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes
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Citation

This paper should be referenced as such :
Laurence Bianchini
Soft Tissues: Ordinary lipoma with t(1;12)(p32;q14) HMGA2/PPAP2B
Atlas Genet Cytogenet Oncol Haematol. 2015;19(11):676-678.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/lipomat0112HMGA2-PPAP2BID6602.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(1;12)(p32;q14) HMGA2/PPAP2B

External links

Mitelman database t(1;12)(p32;q14) HMGA2/PPAP2B [Case List]    t(1;12)(p32;q14) HMGA2/PPAP2B [Association List] Mitelman database (CGAP - NCBI)
arrayMap arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseHMGA2/PPAP2B[MCList]    HMGA2 (12q14.3) PPAP2B (1p32.2)   t(1;12)(p32;q14)
 
Other databaseMitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (2014). Mitelman F, Johansson B and Mertens F (Eds).
Disease databaseSoft Tissues: Ordinary lipoma with t(1;12)(p32;q14) HMGA2/PPAP2B
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed


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