| Written | 2014-12 | Laurence 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 |
| 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 Name | HMGA2 |
| 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 Name | PLPP3 |
| 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 |
| Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains |
| Ashar HR, Fejzo MS, Tkachenko A, Zhou X, Fletcher JA, Weremowicz S, Morton CC, Chada K |
| Cell 1995 Jul 14;82(1):57-65 |
| PMID 7606786 |
| Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype |
| Bartuma H, Hallor KH, Panagopoulos I, Collin A, Rydholm A, Gustafson P, Bauer HC, Brosjö O, Domanski HA, Mandahl N, Mertens F |
| Genes Chromosomes Cancer 2007 Jun;46(6):594-606 |
| PMID 17370328 |
| Identification of PPAP2B as a novel recurrent translocation partner gene of HMGA2 in lipomas |
| Bianchini L, Birtwisle L, Saäda E, Bazin A, Long E, Roussel JF, Michiels JF, Forest F, Dani C, Myklebost O, Birtwisle-Peyrottes I, Pedeutour F |
| Genes Chromosomes Cancer 2013 Jun;52(6):580-90 |
| PMID 23508853 |
| Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15 |
| Broberg K, Zhang M, Strömbeck B, Isaksson M, Nilsson M, Mertens F, Mandahl N, Panagopoulos I |
| Int J Oncol 2002 Aug;21(2):321-6 |
| PMID 12118328 |
| Lipid phosphate phosphatase-3 regulates tumor growth via beta-catenin and CYCLIN-D1 signaling |
| Chatterjee I, Humtsoe JO, Kohler EE, Sorio C, Wary KK |
| Mol Cancer 2011 May 11;10:51 |
| PMID 21569306 |
| The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning |
| Escalante-Alcalde D, Hernandez L, Le Stunff H, Maeda R, Lee HS, Jr-Gang-Cheng, Sciorra VA, Daar I, Spiegel S, Morris AJ, Stewart CL |
| Development 2003 Oct;130(19):4623-37 |
| PMID 12925589 |
| Clinicopathological features of lipomas with gene fusions involving HMGA2 |
| Hatano H, Morita T, Ogose A, Hotta T, Kobayashi H, Segawa H, Uchiyama T, Takenouchi T, Sato T |
| Anticancer Res 2008 Jan-Feb;28(1B):535-8 |
| PMID 18383898 |
| NFIB rearrangement in superficial, retroperitoneal, and colonic lipomas with aberrations involving chromosome band 9p22 |
| Italiano A, Ebran N, Attias R, Chevallier A, Monticelli I, Mainguené C, Benchimol D, Pedeutour F |
| Genes Chromosomes Cancer 2008 Nov;47(11):971-7 |
| PMID 18663748 |
| The tumor suppressor microRNA let-7 represses the HMGA2 oncogene |
| Lee YS, Dutta A |
| Genes Dev 2007 May 1;21(9):1025-30 |
| PMID 17437991 |
| Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation |
| Mayr C, Hemann MT, Bartel DP |
| Science 2007 Mar 16;315(5818):1576-9 |
| PMID 17322030 |
| 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 |
| Cytogenet Genome Res 2006;112(1-2):60-6 |
| PMID 16276091 |
| Fusion of the HMGA2 and NFIB genes in lipoma |
| Nilsson M, Panagopoulos I, Mertens F, Mandahl N |
| Virchows Arch 2005 Nov;447(5):855-8 |
| PMID 16133369 |
| 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 |
| Genomics 1996 Aug 15;36(1):118-29 |
| PMID 8812423 |
| LHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes |
| Petit MM, Schoenmakers EF, Huysmans C, Geurts JM, Mandahl N, Van de Ven WJ |
| Genomics 1999 May 1;57(3):438-41 |
| PMID 10329012 |
| Lack of lipid phosphate phosphatase-3 in embryonic stem cells compromises neuronal differentiation and neurite outgrowth |
| Sànchez-Sànchez R, Morales-Làzaro SL, Baizabal JM, Sunkara M, Morris AJ, Escalante-Alcalde D |
| Dev Dyn 2012 May;241(5):953-64 |
| PMID 22434721 |
| Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours |
| Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJ |
| Nat Genet 1995 Aug;10(4):436-44 |
| PMID 7670494 |
| The 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, Morris AJ, Wolf JK, Fang X, Hasegawa Y, Lapushin R, Auersperg N, Sigal YJ, Newman RA, Felix EA, Atkinson EN, Mills GB |
| Cancer Res 2003 Mar 1;63(5):1073-82 |
| PMID 12615725 |
| Silencing of thrombospondin-1 is critical for myc-induced metastatic phenotypes in medulloblastoma |
| Zhou L, Picard D, Ra YS, Li M, Northcott PA, Hu Y, Stearns D, Hawkins C, Taylor MD, Rutka J, Der SD, Huang A |
| Cancer Res 2010 Oct 15;70(20):8199-210 |
| PMID 20876797 |
| Citation |
| This paper should be referenced as such : |
| Bianchini L |
| Soft Tissues: Ordinary lipoma with t(1;12)(p32;q14) HMGA2/PPAP2 |
| Atlas Genet Cytogenet Oncol Haematol. in press |
| 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 |
| REVIEW articles | automatic search in PubMed |
| Last year articles | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:24:58 CEST 2017 |
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