Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Solid Tumour Section Short Communication Soft Tissues: Ordinary lipoma with t(1;12)(p32;q14) HMGA2/PPAP2B Laurence Bianchini Institute for Research on Cancer, Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, University of Nice-Sophia Antipolis, Nice, France / [email protected] Published in Atlas Database: December 2014 Online updated version : http://AtlasGeneticsOncology.org/Tumors/lipomat0112HMGA2-PPAP2BID6602.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62493/12-2014-lipomat0112HMGA2-PPAP2BID6602.pdf DOI: 10.4267/2042/62493 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology at the molecular level until our report (Bianchini et Abstract al., 2013). Review on lipoma with t(1;12)(p32;q14) Cytogenetics Molecular HMGA2/PPAP2B, with data on clinics, and the genes involved. Rearrangements of HMGA2 and PPAP2B were detected by metaphase FISH mapping using the Keywords dual-color break-apart FISH probes set RP11-30I11 lipoma; translocation; HMGA2; PPAP2B. (HMGA2 5' region) and RP11-118B13 (HMGA2 3' region) and the dual-color break-apart FISH probes Classification set RP11-485A11 (telomeric to the PPAP2B 3' UTR Benign lipomatous neoplasm region) and RP11-20I22 (flanking the PPAP2B 5' UTR region) respectively. Clinics and pathology Genes involved and Disease proteins Ordinary lipoma Note HMGA2 First description of the involvement of PPAP2B in a Location chromosomal translocation 12q14.3 Epidemiology DNA / RNA Ordinary lipomas are the most frequent HMGA2 (formerly HMGI-C) is a member of the mesenchymal human tumors HMGA (high mobility group A) family. The gene is composed of 5 exons and spans approximately 160 Clinics kb. Exons 3 and 4 are separated by a very large intron The tumor presented as a solitary mass (5.5 x 4.5 x (more than 140 kb) where breakpoints have been 2.5 cm) located in the right chest wall. reported to occur preferentially in lipoma cases harbouring HMGA2 rearrangements (Ashar et al., Cytogenetics 1995). Protein Cytogenetics Morphological The protein is composed of 108 amino acid residues. The t(1;12)(p32;q14) translocation had already been It contains three DNA-binding domains (AT-hooks) described in lipomas (Mitelman et al., 2014) in a -encoded by the three first exons- and an acidic limited number of cases but had never been explored carboxy-terminal region -encoded by the fifth exon- Atlas Genet Cytogenet Oncol Haematol. 2015; 19(11) 676 Soft Tissues: Ordinary lipoma with t(1;12)(p32;q14) Bianchini L HMGA2/PPAP2B which may be involved in protein-protein Although more than 40 chromosome bands have interactions. been described in rearrangements involving the HMGA2 is an architectural transcription factor 12q13-15 region in lipomas (Bartuma et al., 2007), which does not have a transcription activity per se only five genes have been identified as fusion but contributes to transcriptional regulation by partners of HMGA2 before PPAP2B: LPP (3q28), remodeling chromatin architecture. CXCR7 (2q37), EBF1 (5q33), LHFP (13q12) and Chromosomal rearrangements involving HMGA2 NFIB (9p22) (Petit et al., 1996; Petit et al., 1999; have been described in various benign tumors mostly Broberg et al., 2002; Nilsson et al., 2005; Nilsson et of mesenchymal origin including lipomas (Ashar et al., 2006; Hatano et al., 2008; Italiano et al., 2008). al., 1995; Schoenmakers et al., 1995). Description PLPP3 The translocation preserves the full coding region of Location HMGA2 so the HMGA2-PPAP2B fusion transcript is predicted to encode a full length HMGA2 protein. 1p32.2 Oncogenesis DNA / RNA The 3' UTR of HMGA2 contains multiple binding PPAP2B is a member of the phosphatidic acid sites for the let-7 family. Targeted mutations of phosphatase (PAP) gene family. The PPAP2B gene these binding sites or functional inactivation of let-7 contains 6 exons and spans more than 84 kb. result in upregulation of HMGA2 (Lee and Dutta, Protein 2007; Mayr et al., 2007). We have observed that the The protein (311 amino acids and 35 kDa) encoded t(1;12)(p32;q14) translocation results in a strong by the PPAP2B gene is LPP3 a member of the lipid HMGA2 overexpression both at the mRNA and phosphate phosphatase (LPP) family. protein levels. Our results therefore confirm the LPPs are enzymes that catalyze the hypothesis that HMGA2 overexpression can be dephosphorylation of lipid phosphates including induced by removal of the let-7 binding sites in phosphatidate and lysophosphatidic acid. LPP3 is a HMGA2 3' UTR. Additional studies must be glycoprotein containing 6 transmembrane regions performed to clarify whether PPAP2B plays a role in and three catalytic domains. the tumorigenesis of t(1;12) lipoma. LPP3 has been reported to be involved in vasculogenesis (Escalante-Alcalde et al., 2003), References neuron differentiation and neurite outgrowth (Sanchez-Sanchez et al., 2012). Mitelman F, Johansson B and Mertens F (Eds).. Mitelman Database of Chromosome Aberrations and Gene Fusions Only a limited number of studies have reported the in Cancer (2014) potential involvement of LPP3 in tumorigenesis http://cgap.nci.nih.gov/Chromosomes/Mitelman (Tanyi et al., 2003; Zhou et al., 2010; Chatterjee et Ashar HR, Fejzo MS, Tkachenko A, Zhou X, Fletcher JA, al., 2011). Weremowicz S, Morton CC, Chada K. Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs Result of the chromosomal fused in lipomas to distinct transcriptional regulatory domains Cell 1995 Jul 14;82(1):57-65 anomaly Bartuma H, Hallor KH, Panagopoulos I, Collin A, Rydholm A, Gustafson P, Bauer HC, Brosjö O, Domanski HA, Hybrid Gene Mandahl N, Mertens F. Assessment of the clinical and Description molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype Genes The t(1;12)(p32;q14) in this lipoma case results in a Chromosomes Cancer 2007 Jun;46(6):594-606 chimeric HMGA2-PPAP2B transcript fusioning Bianchini L, Birtwisle L, Saäda E, Bazin A, Long E, Roussel HMGA2 3' untranslated region (UTR) with PPAP2B JF, Michiels JF, Forest F, Dani C, Myklebost O, Birtwisle- exon 6. Peyrottes I, Pedeutour F. Identification of PPAP2B as a The breakpoint in HMGA2 3' UTR is located novel recurrent translocation partner gene of HMGA2 in downstream of the first let-7 microRNA binding site. lipomas Genes Chromosomes Cancer 2013 Jun;52(6):580- 90 Detection Broberg K, Zhang M, Strömbeck B, Isaksson M, Nilsson M, The chromosomal breakpoints of the Mertens F, Mandahl N, Panagopoulos I. Fusion of RDC1 t(1;12)(p32;q14) were first defined using a FISH- with HMGA2 in lipomas as the result of chromosome based positional cloning strategy followed by RT- aberrations involving 2q35-37 and 12q13-15 Int J Oncol PCR to detect potential fusion transcripts. RT-PCR 2002 Aug;21(2):321-6 products have been finally sequenced using traditional Sanger sequencing. Chatterjee I, Humtsoe JO, Kohler EE, Sorio C, Wary KK. Fusion Protein Lipid phosphate phosphatase-3 regulates tumor growth via beta-catenin and CYCLIN-D1 signaling Mol Cancer 2011 Note May 11;10:51 Atlas Genet Cytogenet Oncol Haematol. 2015; 19(11) 677 Soft Tissues: Ordinary lipoma with t(1;12)(p32;q14) Bianchini L HMGA2/PPAP2B Escalante-Alcalde D, Hernandez L, Le Stunff H, Maeda R, Petit MM, Schoenmakers EF, Huysmans C, Geurts JM, Lee HS, Jr-Gang-Cheng, Sciorra VA, Daar I, Spiegel S, Mandahl N, Van de Ven WJ. LHFP, a novel translocation Morris AJ, Stewart CL. The lipid phosphatase LPP3 partner gene of HMGIC in a lipoma, is a member of a new regulates extra-embryonic vasculogenesis and axis family of LHFP-like genes Genomics 1999 May patterning Development 2003 Oct;130(19):4623-37 1;57(3):438-41 Hatano H, Morita T, Ogose A, Hotta T, Kobayashi H, Sànchez-Sànchez R, Morales-Làzaro SL, Baizabal JM, Segawa H, Uchiyama T, Takenouchi T, Sato T. Sunkara M, Morris AJ, Escalante-Alcalde D. Lack of lipid Clinicopathological features of lipomas with gene fusions phosphate phosphatase-3 in embryonic stem cells involving HMGA2 Anticancer Res 2008 Jan- compromises neuronal differentiation and neurite outgrowth Feb;28(1B):535-8 Dev Dyn 2012 May;241(5):953-64 Italiano A, Ebran N, Attias R, Chevallier A, Monticelli I, Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van Mainguené C, Benchimol D, Pedeutour F. NFIB den Berghe H, Van de Ven WJ. Recurrent rearrangements rearrangement in superficial, retroperitoneal, and colonic in the high mobility group protein gene, HMGI-C, in benign lipomas with aberrations involving chromosome band 9p22 mesenchymal tumours Nat Genet 1995 Aug;10(4):436-44 Genes Chromosomes Cancer 2008 Nov;47(11):971-7 Tanyi JL, Morris AJ, Wolf JK, Fang X, Hasegawa Y, Lee YS, Dutta A. The tumor suppressor microRNA let-7 Lapushin R, Auersperg N, Sigal YJ, Newman RA, Felix EA, represses the HMGA2 oncogene Genes Dev 2007 May Atkinson EN, Mills GB. The human lipid phosphate 1;21(9):1025-30 phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the Mayr C, Hemann MT, Bartel DP. Disrupting the pairing lysophosphatidic acid signaling cascade as a target for between let-7 and Hmga2 enhances oncogenic therapy in ovarian cancer Cancer Res 2003 Mar transformation Science 2007 Mar 16;315(5818):1576-9 1;63(5):1073-82 Nilsson M, Mertens F, Höglund M, Mandahl N, Zhou L, Picard D, Ra YS, Li M, Northcott PA, Hu Y, Stearns Panagopoulos I. Truncation and fusion of HMGA2 in D, Hawkins C, Taylor MD, Rutka J, Der SD, Huang A. lipomas with rearrangements of 5q32-->q33 and 12q14-- Silencing of thrombospondin-1 is critical for myc-induced >q15 Cytogenet Genome Res 2006;112(1-2):60-6 metastatic phenotypes in medulloblastoma Cancer Res Nilsson M, Panagopoulos I, Mertens F, Mandahl N.