Benign lipomatous neoplasm

First description of the involvement of PPAP2B in a chromosomal translocation

Ordinary lipomas are the most frequent mesenchymal human tumors

The tumor presented as a solitary mass (5.5 x 4.5 x 2.5 cm) located in the right chest wall.

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).

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.

HMGA2 (high mobility group AT-hook 2)

12q14.3

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).

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).

PLPP3 (phospholipid phosphatase 3)

1p32.2

PPAP2B is a member of the phosphatidic acid phosphatase (PAP) gene family. The PPAP2B gene contains 6 exons and spans more than 84 kb.

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).

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.

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.

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).

The translocation preserves the full coding region of HMGA2 so the HMGA2-PPAP2B fusion transcript is predicted to encode a full length HMGA2 protein.

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.