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The Recurrent Chromosomal Translocation T(12;18) (Q14~15;Q12~21) Causes the Fusion Gene HMGA2-SETBP1 and HMGA2 Expression in Lipoma and Osteochondrolipoma

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The Recurrent Chromosomal Translocation T(12;18) (Q14~15;Q12~21) Causes the Fusion Gene HMGA2-SETBP1 and HMGA2 Expression in Lipoma and Osteochondrolipoma 884 INTERNATIONAL JOURNAL OF ONCOLOGY 47: 884-890, 2015 The recurrent chromosomal translocation t(12;18) (q14~15;q12~21) causes the fusion gene HMGA2-SETBP1 and HMGA2 expression in lipoma and osteochondrolipoma IOANNIS PANAGOPOULOS1,2, LUDMILA GORUNOVA1,2, BODIL BJERKEHAGEN3, INGVILD LOBMAIER3 and SVERRE HEIM1,2,4 1Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo; 2Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo; 3Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo; 4Faculty of Medicine, University of Oslo, Oslo, Norway Received April 21, 2015; Accepted June 8, 2015 DOI: 10.3892/ijo.2015.3099 Abstract. Lipomas are the most common soft tissue tumors to the findings in the much more common ordinary lipomas, in adults. They often carry chromosome aberrations involving underscores the close developmental relationship between the 12q13~15 leading to rearrangements of the HMGA2 gene in two tumor types. 12q14.3, with breakpoints occurring within or outside of the gene. Here, we present eleven lipomas and one osteochondro- Introduction lipoma with a novel recurrent chromosome aberration, t(12;18) (q14~15;q12~21). Molecular studies on eight of the tumors Lipomas are benign tumors composed of mature fat cells (1). showed that full-length HMGA2 transcript was expressed in It is the most common soft tissue tumor in adults with peak three and a chimeric HMGA2 transcript in five of them. In incidence between 40-60 years. They may appear at any site three lipomas and in the osteochondrolipoma, exons 1-3 of but with a broad distinction between subcutaneous (superfi- HMGA2 were fused to a sequence of SETBP1 on 18q12.3 or cial) and deep-seated lesions. Although most lipomas are an intragenic sequence from 18q12.3 circa 10 kbp distal to easily diagnosed, those occurring deep down (e.g., intra- SETBP1. In another lipoma, exons 1-4 of HMGA2 were fused muscular lipoma, perineural lipoma) may be confused with to an intronic sequence of GRIP1 which maps to chromosome liposarcomas. Though mitoses are rarely seen in histologic band 12q14.3, distal to HMGA2. The ensuing HMGA2 fusion sections of lipomas, karyotypes can easily be obtained from transcripts code for putative proteins which contain amino acid short-term cultured tumor cells. In 1986, the first characteristic residues of HMGA2 corresponding to exons 1-3 (or exons 1-4 acquired chromosome aberration of lipomas was described, in one case) followed by amino acid residues corresponding to the translocation t(3;12)(q27~28;q13~15) (2,3). Since then, the fused sequences. Thus, the pattern is similar to the rear- according to the Mitelman Database of Chromosome rangements of HMGA2 found in other lipomas, i.e., disruption Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih. of the HMGA2 locus leaves intact exons 1-3 which encode the gov/Chromosomes/Mitelman database updated on February AT-hooks domains and separates them from the 3'-terminal 13, 2015), 476 lipomas with chromosome aberrations have been part of the gene. The fact that the examined osteochondroli- reported, with involvement of chromosome bands 12q13~15 poma had a t(12;18) and a HMGA2-SETBP1 fusion identical being seen in more than 300 of them. Recombination may take place with a wide variety of partners, but the by far most common is the translocation t(3;12)(q27~28;q14~15) which has been reported in 53 of the aberrant karyotypes registered in the Mitelman Database. Other recurrently involved chromo- Correspondence to: Dr Ioannis Panagopoulos, Section for Cancer some segments found recombined with 12q13~15 in lipomas Cytogenetics, Institute for Cancer Genetics and Informatics, The are 1p36 and 1p32~34 (each found in 29 cases), 2p22~24 (in 6 Norwegian Radium Hospital, Oslo University Hospital, P.O. Box cases), 2q35~37 (10 cases), 5q33 (16 cases), 9p21~22 (7 cases) 4953 Nydalen, NO-0424 Oslo, Norway and 12p11~13 and 13q12~14 (8 cases each). The chromosome E-mail: [email protected] rearrangements often target the HMGA2 gene in 12q14.3 with Key words: lipoma, osteochondrolipoma, t(12;18)(q14~15;q12~21), breakpoints occurring both within and outside the locus; the recurrent chromosomal translocation, HMGA2-SETBP1, HMGA2 essential outcome appears to be deregulation of HMGA2 with expression truncation of the gene as the critical event (4 and refs. therein). The most frequent translocation, t(3;12)(q27~28;q13~15), generates an HMGA2-LPP fusion gene coding for a transcrip- tion factor containing the AT-hook domain of HMGA2 and ACKR3 been reported with genes to form fusion C-terminal LIM domains LPP of the expression level of of level theexpression PCR. Real-time Both male are anddonors female represented. genes. expressed abroad rangeof to represent chosen tissues, amixtureis total of human RNAs adult from of acollection information,it to the According company's France). en-Laye, Saint-Germain- Group, Bio Laboratories, Takara (Clontech used RNA as was control Total Reference Human Universal The real-time inused PCR as subsequent template assays. to 10 equivalent cDNA Norway). the manufacturer's instructions (Bio-Rad Laboratories, Oslo, according to RT-qPCR kit for Synthesis cDNA Advanced reverse-transcribed in 20 a 400-500 synthesis, cDNA For Sweden). Stockholm, manufacturer's Nordic, recommendations (Qiagen II and accordingQiacube homogenizer to the TissueLyser kit, extracted miRNeasy RNA was using Total 1-8). tumors (cases examination had been frozen and stored at -80˚C from eight and histologic analysis to cytogenetic that used for adjacent RNA isolation Total and synthesis. cDNA ISCN karyotype the recommendations the of description followed and analysis stain. cytogenetic The Wright subsequent using The cultures harvested were and the G-banded chromosomes gated and short-term cultured as described elsewhere specimensmechanically were and enzymatically disaggre Chromosome banding analysis. All the tumors tumor. of the surgically location removed. were Patients. written informed obtained was consent from the patients. setikk http://helseforskning.etikkom.no) Norge, Sør-Øst, and ethics committee medisinsk forskning for komité (Regional Ethics statement. methods and Materials benign celland moleculartumors. in consequences its fat 12 recurrent chromosome translocation, t(12;18)(q14~15;q12~21) (at Mix Master Universal contained TaqMan 1X reaction volume The 20 control. used as was endogenous Hs99999903_m1, The used. were 4-5) (HMGA2 exons ( Hs00171569_m1 USA) CA, City, Foster Biosystems, (Applied assays sion software (Bio-Rad Laboratories). 60˚C. The data were analyzed using Bio-Rad CFX Manager by 10 cycling included an initial step at 50˚C for 2 The thermal (Bio-Rad Laboratories). PCR Detection System Real-Time Real-time PCR run was aCFX96 on Touch™ performed. were control and sample the each endogenous of M ix, andix, 1 13q12) II with UNG, lX of the 20X TaqMan TaqMan II lX the UNG, with 20X of (13). min at 40 95˚C, of cycles 15 (at 2q37), 2q37), (at Table µl cDNA (10 cDNA µl (7-11). In the present study, we describe a novel describe we anovel In the study, present (7-11). I shows the patients' gender, age, diagnosis and diagnosis age, gender, the patients' I shows Real-time PCR carried was to determine out The study was approved by the regional the regional by approved The was study HMGA2 EBF1 P anagopoulos HMGA2 (at 5q33), 5q33), (at ng equivalent of RNA). Four replicates Four replicates RNA). of equivalent ng exons 1-2) and Hs00971725_m1 and Hs00971725_m1 1-2) exons µl reaction volume using iScript iScript using reaction volume µl Samples from theSamples operation . The TaqMan gene expres gene The . TaqMan NFIB (5,6). (5,6). sec at and95˚C 1 ng/µl of total RNA was total of RNA was ng/µl et al (at 9p22) and 9p22) (at ng of total of ng RNA were ACTB : HMGA2 PPAP2 t G (12;18)( ene min, followed min, followed Tumor tissue tissue Tumor gene, assay E q (at 1p32), 14~15; xpression has also min at LHFP (12). (12). q 12~21) 12~21) µl µl - - - in Table I. Clinical, cytogenetic and molecular data on the 12 benign fat cell tumors. lipoma Case Gender/ Cq, Ex1-Ex2 Cq, Ex4-Ex5 Cq of HMGA2 no. age (years) Diagnosis Location Karyotype of HMGA2 of HMGA2 ACTB fusion and osteochondrolipoma 1 M/58 Lipoma Intramuscular, left thigh 46,XY,t(12;18)(q14~q15;q12~q21)[12]/46,XY[3] 30.97 28.23 23.41 Not done 2 F/44 Lipoma Intramuscular, right elbow 46,XX,t(12;18)(q14~q15;q12~q21)[16] 29.76 27.58 25.27 Not done 3 M/54 Lipoma Intramuscular, right deltoid 46,XY,t(12;18)(q14~q15;q12~q21)[12]/46,XY[3] 28.58 36.84 24.33 HMGA2-sequence from 18q12.3 4 F/34 Lipoma Intramuscular, right deltoid 46,XX,t(12;18)(q14~q15;q12~q21)[14] 30.10 39.69 24.33 HMGA2-SETBP1 5 M/38 Lipoma Left thoracic wall 46,XY,t(12;18)(q14~q15;q12~q21)[15] 28.73 38.84 22.45 HMGA2-GRIP1 6 F/28 Lipoma Intramuscular, left thigh 46,XX,t(12;18)(q14~q15;q12~q21)[14]/46,XX[1] 32.57 30 22.96 Not done 7 F/61 Lipoma Intramuscular, right 46,XX,t(12;18)(q14~q15;q12~q21)[12]/46,XX[3] 26.28 39.36 23.67 HMGA2-SETBP1 splenius capitis muscle 8 M/55 Osteochon- Intramuscular, subscapularis 46,XY,t(12;18)(q14~q15;q12~q21)[15] 30.04 35.64 24.97 HMGA2-SETBP1 drolipoma muscle 9 M/55 Lipoma Intramuscular, right 46,XY,t(2;18;12)(q37;q12~q21;q14~15)[9] Not done Not done Not done Not done infraspinatus muscle 10 M/15 Lipoma Foot, right intrametatarsal 46,XY,t(12;18)(q14~q15;q12~q21)[15] Not done Not done Not done Not done 11 M/64 Lipoma Right groin 46,XY,t(8;9)(p21;q22),t(12;18)(q14~q15;q12~q21)[10] Not done Not done Not done Not done 12 M/56 Lipoma Intramuscular, left deltoid 46,XY,t(12;18)(q14~q15;q12~q21)[5]/46,XY[5] Not done Not done Not done Not done 885 886 INTERNATIONAL JOURNAL OF ONCOLOGY 47: 884-890, 2015 3'-Rapid amplification cDNA ends (3'-RACE).
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