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

2014-12-01   Laurence Bianchini 

1.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

Abstract

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

Classification

Classification

Benign lipomatous neoplasm

Clinics and Pathology

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 name

HMGA2 (high mobility group AT-hook 2)

Location

12q14.3

Dna rna description

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 description

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 name

PLPP3 (phospholipid phosphatase 3)

Location

1p32.2

Dna rna description

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 description

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

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 protocole

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.

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

Pubmed IDLast YearTitleAuthors
76067861995Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains.Ashar HR et al
173703282007Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype.Bartuma H et al
235088532013Identification of PPAP2B as a novel recurrent translocation partner gene of HMGA2 in lipomas.Bianchini L et al
121183282002Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15.Broberg K et al
215693062011Lipid phosphate phosphatase-3 regulates tumor growth via β-catenin and CYCLIN-D1 signaling.Chatterjee I et al
129255892003The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning.Escalante-Alcalde D et al
183838982008Clinicopathological features of lipomas with gene fusions involving HMGA2.Hatano H et al
186637482008NFIB rearrangement in superficial, retroperitoneal, and colonic lipomas with aberrations involving chromosome band 9p22.Italiano A et al
174379912007The tumor suppressor microRNA let-7 represses the HMGA2 oncogene.Lee YS et al
173220302007Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation.Mayr C et al
162760912006Truncation and fusion of HMGA2 in lipomas with rearrangements of 5q32-->q33 and 12q14-->q15.Nilsson M et al
161333692005Fusion of the HMGA2 and NFIB genes in lipoma.Nilsson M et al
88124231996LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family.Petit MM et al
103290121999LHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes.Petit MM et al
224347212012Lack of lipid phosphate phosphatase-3 in embryonic stem cells compromises neuronal differentiation and neurite outgrowth.Sánchez-Sánchez R et al
76704941995Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours.Schoenmakers EF et al
126157252003The human lipid phosphate phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid signaling cascade as a target for therapy in ovarian cancer.Tanyi JL et al
208767972010Silencing of thrombospondin-1 is critical for myc-induced metastatic phenotypes in medulloblastoma.Zhou L et al

Citation

Laurence Bianchini

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

Atlas Genet Cytogenet Oncol Haematol. 2014-12-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/6602/soft-tissues-ordinary-lipoma-with-t(1;12)(p32;q14)-hmga2-ppap2b