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Fusion, Disruption, and Expression of HMGA2 in Bone and Soft Tissue

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Fusion, Disruption, and Expression of HMGA2 in Bone and Soft Tissue Fusion, Disruption, and Expression of HMGA2 in Bone and Soft Tissue Chondromas Anna Dahlén, Fredrik Mertens, M.D., Anders Rydholm, M.D., Otte Brosjö, M.D., Johan Wejde, M.D., Nils Mandahl, Ph.D., Ioannis Panagopoulos, Ph.D. Department of Clinical Genetics (AD, FM, NM, IP) and Department of Orthopedics (AR), University Hospital, Lund; and Department of Orthopedics (OB) and Department of Pathology (JW), Karolinska Hospital, Stockholm, Sweden found in 8 of 13 chondrosarcomas, 4 of which dis- Soft tissue and skeletal chondromas are rare enti- played 12q rearrangements. Possibly, cryptic rear- ties, and only 21 cases with abnormal karyotypes rangements were present among the many complex have been reported. A survey of these, and 10 new marker chromosomes in the remaining 4 cases. cases reported herein, showed that the 12q13–15 segment is nonrandomly involved in structural re- KEY WORDS: Chondroma, Chondrosarcoma, FISH, arrangements in chondromas. The HMGA2 HMGA2, HMGA2-LPP, RT-PCR. (HMGI-C) locus in 12q15 is frequently rearranged in Mod Pathol 2003;16(11):1132–1140 other benign mesenchymal tumors, and this study aimed at characterizing the expression of HMGA2 in Benign cartilage tumors (enchondromas and peri- chondromatous tumors. The material consisted of 8 osteal chondromas) represent some 10–25% of all soft tissue and 6 skeletal chondromas, as well as of primary bone tumors. Enchondromas typically oc- 14 skeletal chondrosarcomas. All cases had been cur in the small tubular bones of the hands and cytogenetically analyzed. Expression of HMGA2 feet, whereas the rare periosteal chondromas pre- could be assessed by RT-PCR in 8 chondromas and dominantly appear on the surface of the long tubu- 13 chondrosarcomas. HMGA2 was expressed in 4of lar bones (1). Soft tissue chondromas (extraskeletal six soft tissue chondromas, all displaying 12q- chondromas), which have no connection to the un- rearrangements at cytogenetic analysis. A truncated derlying bone or periosteum, are rare, and close to transcript (exons 1–3), but not a full-length (exons two thirds of these tumors are found in the fingers 1–5) transcript, was detected in three of them, sug- (2). The variable histological appearance of benign gesting activation through an intragenic rearrange- chondromatous tumors often makes the distinction ment. One soft tissue chondroma had a t(3;12)(q27; from low-grade chondrosarcoma difficult, and clin- q15), and the RT-PCR analysis revealed an HMGA2- ical features and radiological findings are often LPP fusion transcript, composed of HMGA2 exons needed to reach a correct diagnosis. Only 21 cyto- 1–3 and LPP exons 9–11. An identical fusion tran- genetically abnormal bone and soft tissue chondro- script previously has been identified in lipoma and mas have been published (3; December 2002), re- pulmonary chondroid hamartoma. In the fourth stricting the possibilities of relating the clonal soft tissue chondroma, a full-length transcript was chromosomal aberrations to a particular pathologic detected, indicating expression of at least one intact subtype. Furthermore, most studies of chondromas allele. Both skeletal chondromas expressed HMGA2. have presented small series, with many cases show- In one of them, a full-length transcript was de- ing normal karyotypes or nonclonal changes only tected, even though 12q was cytogenetically unaf- (4–7). fected. A truncated or full-length transcript was Chromosome region 12q13–15 is frequently in- volved in structural rearrangements in a number of benign mesenchymal tumors, such as uterine Copyright © 2003 by The United States and Canadian Academy of leiomyoma, lipoma, and pulmonary chondroid Pathology, Inc. VOL. 16, NO. 11, P. 1132, 2003 Printed in the U.S.A. hamartoma, as well as in pleomorphic salivary Date of acceptance: July 14, 2003. This work was supported by the Swedish Cancer Society and the Swedish gland adenoma (3). Molecular genetic analyses Childrens’ Cancer Foundation. have disclosed that a common target for these re- Address reprint requests to: Anna Dahlén, Department of Clinical Genet- ics, University Hospital, SE-221 85, Lund, Sweden; fax: 46 46 13 10 61; arrangements is the HMGA2 (HMGI-C) gene located e-mail: [email protected]. in 12q15 (8–10). The HMGA2 protein is a member DOI: 10.1097/01.MP.0000092954.42656.94 of the high–mobility group A (HMGA) proteins, 1132 which are small, nonhistonic, chromatin- 63 y). The chondromas represented all such tumors associated proteins. These proteins are believed to collected at our department during the last 15 years affect transcription as architectural elements by and from which material for expression analysis bending the DNA and by interacting with a large was available. The chondrosarcoma samples were number of other proteins, mainly transcription fac- selected to represent different cytogenetic sub- tors, but also to influence chromatin changes dur- groups (22). One (Case 15) was a peripheral chon- ing the cell cycle (11). The HMGA2 gene is highly drosarcoma, whereas the remaining 13 tumors (and ubiquitously) expressed in embryonic tissues, were central. Nine tumors were classified as pri- but even though expression of HMGA2 has only mary (conventional), four as dedifferentiated (Cas- been detected in adult kidney, lung, and synovia es 23–26), and one (Case 27) as a clear cell chon- (12, 13), HMGA2 is expected to have a role in adult drosarcoma. One chondroma and three tissues as well (11). The HMGA2 gene has five ex- chondrosarcomas were local recurrences; all other ons, and the first three, each encoding a DNA- samples were from primary tumors. binding domain, are separated from the last two exons by a large intron (14). Rearrangements of Cytogenetic Analysis HMGA2 in mesenchymal tumors often result in the in-frame fusion of the three first exons to an ectopic Culturing, harvesting, and G-banding were per- sequence, giving rise to a chimeric protein that may formed as described (23), and the karyotypes were have an impact on transcription of other genes (8, written according to the recommendations of the 11, 15). It has been proposed that lack of the ISCN (24). The karyotypes of four of the chondro- HMGA2 3'-terminal, rather than the acquisition of mas and seven of the chondrosarcomas have been new sequences, causes the altered phenotype. In- published (4, 7, 21, 22). deed, expression of truncated HMGA2 is associated with gigantism and adipose tissue hyperplasia in RNA Extraction and cDNA Synthesis transgenic mice (16), as well as with transformation Total RNA was extracted from frozen tumor tis- of NIH3T3 mouse cell lines (17). However, in some sue using the Trizol-reagent according to the man- tumor types, notably uterine leiomyomas, expres- ufacturer’ recommendations (Gibco BRL, Täby, sion of a full-length transcript rather than the cre- Sweden). ation of a fusion gene is the typical outcome of For the synthesis of cDNA, 1.2–5 ␮g of total RNA 12q13–15 rearrangements (18). Furthermore, it has was initially incubated for 10 minutes at 65° C. For been shown in experimental models that also the a 20-␮L reaction, a mix containing 50 mM Tris-HCl, full-length transcipt, when aberrantly expressed, pH 8.3 (at 25° C), 75 mM KCl, 3 mM MgCl ,10mM may induce neoplastic growth (19). Thus, it pres- 2 DTT, 1 mM of each dNTP, 0.5 pM Random Hexam- ently seems as if both full-length and truncated ers, and 28 U RNAse inhibitor (RNA guard, Amer- HMGA2 transcripts may be oncogenic. sham), was then added. Finally, 400 U of M-MLV It has been suggested that rearrangements of Reverse Transcriptase (Invitrogen, Stockholm, Swe- chromosome bands 12q13–15 are characteristic for den) was added, and the reaction was incubated for a subgroup of chondromas (4, 5, 20, 21), but so far 1 hour at 37° C, followed by incubation for 5 min- the status of the HMGA2 gene has not been studied utes at 65° C. As an internal control of cDNA quality, in these neoplasms. The aim of the present study 1 ␮L of cDNA was amplified by polymerase chain was to analyze the expression of full-length and reaction (PCR) using Actin B-specific primers (Ta- truncated HMGA2 in a series of cytogenetically an- ble 2) (25). alyzed soft tissue and bone chondromas. For com- parison with the expression pattern in malignant chondromatous neoplasms, we also included chon- HMGA2 Expression Analysis drosarcomas representing different cytogenetic HMGA2 transcripts were detected by reverse- subgroups. transcribed PCR (RT-PCR), and the nucleotide se- quences for all primers used are presented in Table 2. Transcripts of HMGA2 exons 1–3 were detected MATERIALS AND METHODS with primers HMG848(F) and HMG1021(R). Tran- scripts for HMGA2 exons 1–5 were detected with Patients primers HMG848(F) and HMG1169(R). The material consisted of 8 soft tissue and 6 skel- For the PCR, 1 ␮L of single-stranded cDNA was etal chondromas, as well as 14 skeletal chondrosar- used as a template. The 50-␮L reaction contained comas (Table 1). The chondroma patients (five 20 mM Tris-HCl, 50 mM KCl, 1.25 mM MgCl2, 0.8 mM women, nine men) were 13–74 years old (median, dNTPs, 0.5 ␮M of each primer, and 1U Platinum Taq 53 y), and the chondrosarcoma patients (six DNA Polymerase (Invitrogen). Denaturation for 5 women, eight men) were 28–80 years old (median, minutes at 95° C was followed by 35 cycles of 30 HMGA2 Expression in Chondromas (A. Dahlén et al.) 1133 1134 Modern Pathology TABLE 1. Clinical Data and Cytogenetic Findings in 14 Chondromas and 14 Chondrosarcomas Case Sex/Age Site Karyotypea Soft tissue chondroma 1 F/56 Knee 46,XX,ins(4;12)(q3?4;q1?5q2?3)[17]
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