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Oncogene (2006) 25, 7106–7116 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ONCOGENOMICS Genomic profiling of bone and soft tissue tumors with supernumerary ring chromosomes using tiling resolution bacterial artificial chromosome microarrays M Heidenblad1, KH Hallor1, J Staaf2,GJo¨ nsson2,A˚ Borg2,MHo¨ glund1, F Mertens1 and N Mandahl1 1Department of Clinical Genetics, Lund University Hospital, Lund, Sweden; and 2Department of Oncology, Lund University Hospital, Lund, Sweden Ring chromosomes and/or giant marker chromosomes Keywords: sarcoma; array-based CGH; genome-wide; have been observed in a variety of human tumor types, but gene amplification; ring chromosome they are particularly common in a subgroup of mesen- chymal tumors of low-grade or borderline malignancy. These rings and markers have been shown to contain amplified material predominantly from 12q13–15, but also sequences from other chromosomes. Such amplified Introduction sequences were mapped in detail by genome-wide array comparative genomic hybridization in ring-containing Several bone and soft tissue tumor entities are characte- tumor samples from soft tissue (n ¼ 15) and bone rized cytogenetically by supernumerary ring chromosomes (n ¼ 6), using tiling resolution microarrays, encompassing or giant rod marker chromosomes in karyotypes with 32 433 bacterial artificial chromosome clones. The DNA few or no other chromosome aberrations (Mitelman copy number profiles revealed multiple amplification et al., 2005). The majority of these tumors are low-grade targets, in many cases highly discontinuous, leading to malignant neoplasms that include well-differentiated delineation of large numbers of very small amplicons. A liposarcoma/atypical lipomatous tumor (ALT), subgroups total number of 356 (median size: 0.64 Mb) amplicons of malignant fibrous histiocytoma (MFH), myxofibro- were seen in the soft tissue tumors and 90 (median size: sarcoma, parosteal osteosarcoma and dermatofibrosar- 1.19 Mb) in the bone tumors. Notably, more than 40% of coma protuberans (DFSP). The origin of the ring all amplicons in both soft tissue and bone tumors were chromosomes, which frequently vary in number and mapped to chromosome 12, and at least one of the size between cells from the same tumor, cannot be previously reported recurrent amplifications in 12q13.3– disclosed by chromosome banding techniques owing 14.1 and 12q15.1, including SAS and CDK4, and MDM2, to the diffuse banding pattern and morphological respectively, were present in 85% of the soft tissue tumors variability. Fluorescence in situ hybridization (FISH) and in all of the bone tumors. Although chromosome 12 analyses have revealed that these structures, in most was the only chromosome displaying recurrent amplifica- cases, contain material from chromosome 12, apart tion in the bone tumors, the soft tissue tumors frequently from in DFSP where chromosome 17 and 22 sequences, showed recurrent amplicons mapping to other chromo- including the PDGFB/COL1A1 fusion gene, are present somes, that is, 1p32, 1q23–24, 3p11–12, 6q24–25 and in rings (Dal Cin et al., 1993; Szymanska et al., 1996; 20q11–12. Of particular interest, amplicons containing Chibon et al., 2002; Sirvent et al., 2003). With few excep- genes involved in the c-jun NH2-terminal kinase/mitogen- tions, it is the central part of the long-arm of chromo- activated protein kinase pathway, that is, JUN in 1p32 some 12 (12q) that is present in multiple copies in the ONCOGENOMICS and MAP3K7IP2 (TAB2) in 6q24–25, were found to be ring chromosomes. The amplifications may be discon- independently amplified in eight of 11 cases with 12q tinuous and vary in size, but frequently include chromo- amplification, providing strong support for the notion that some bands 12q14 and 12q15 (Berner et al., 1996). The aberrant expression of this pathway is an important step MDM2 gene is always amplified, whereas several other in the dedifferentiation of liposarcomas. genes, such as SAS, GLI, CDK4 and HMGA2, are Oncogene (2006) 25, 7106–7116. doi:10.1038/sj.onc.1209693; frequently coamplified (Meltzer et al., 1991; Nilbert published online 29 May 2006 et al., 1994; Pedeutour et al., 1994; Gamberi et al., 2000; Gisselsson et al., 2002). The composition of the ring and giant marker Correspondence: Dr M Heidenblad, Department of Clinical Genetics, chromosomes is often quite complex and may include Lund University Hospital, Lund SE-221 85, Sweden. E-mail: [email protected] material from two or more chromosomes. Apart Received 3 January 2006; revised 3 March 2006; accepted 18 April 2006; from the inclusion of chromosome 12 material, direct published online 29 May 2006 evidence through FISH analysis has shown that a Genomic profiling of bone and soft tissue tumors M Heidenblad et al 7107 variety of chromosomes may be involved, in particular amplicons per sample). The number of chromosomes chromosome 1 (Pedeutour et al., 1994; Forus et al., involved in amplification in each case varied from 1 to 1995a; Meza-Zepeda et al., 2001; Nilsson et al., 2004). 14 (case 9); only chromosome 4 was never involved. Similarly, indirect evidence has been obtained from Analysis of primary tumor data from all 19 patients on chromosome-based comparative genomic hybridization average indicated a higher amplification frequency in the (CGH) (Pedeutour et al., 1999; Chibon et al., 2002; soft tissue tumors than in the bone tumors (23 vs 15 Micci et al., 2002; Coindre et al., 2004). The profiles of amplicons per case). Moreover, the analysis showed that genomic imbalances show many similarities between amplicon sizes were significantly smaller among the ALT, dedifferentiated liposarcoma (DDLS) and MFH, former (median size: 0.64 Mb) than among the latter which all share amplification of 12q14–15 in practically (median size: 1.19 Mb; Po0.01, Mann–Whitney U-test). all cases, and in which gain of 1q21–23 is common. Neither the number nor the distribution of amplicons However, also some distinct differences have been distinguished the four soft tissue tumors that meta- reported (Chibon et al., 2002). For example, gain of stasized from those that did not, or the high-grade from sequences from 1p32, 6q23 and 12q24 were absent or the low-grade osteosarcomas. very rare in ALT but fairly common among the other Regarding the genomic localization of the amplicons, soft tissue tumor types. Available data indicate a consi- chromosome 12 was by far most frequently affected derable biological overlap between low-grade MFH (17 of 19 cases), harboring more than 40% of the and lipomatous tumors (Chibon et al., 2002; Coindre amplicons in both tumor groups. In the soft tissue et al., 2003). Based on chromosome CGH data, the 12q tumors, also chromosomes 1 and 6 were commonly amplicon extends from 12q13 to 12q21 in most cases, affected, containing 25 and 6% of the amplicons in with a peak in 12q14 and 12q15, but may occasionally this group, respectively. Apart from chromosome 12, include both more distal and more proximal regions. the only chromosome amplified in more than one bone The 1q amplicon is usually located between 1q21 and tumor was chromosome 5. However, this chromo- 1q25 with a peak incidence in 1q23, whereas the 1p some did not contain any overlapping amplicons. A amplicon seems to be narrow and commonly includes complete description of all amplicons is available only 1p32. in Supplementary Table 1. In the present study, soft tissue and bone tumors To identify genomic regions likely to contain genes of with ring and/or giant marker chromosomes and few or importance for tumor development, a list of recurrent no other chromosome aberrations were investigated by amplifications was compiled (Table 2). In the soft tissue array CGH. For this purpose we used whole-genome tumors, segments amplified in 2–11 of 13 cases were tiling resolution bacterial artificial chromosome (BAC) identified in 1p, 1q, 3p, 6q, 12p, 12q and 20q. Because of microarrays, encompassing 32 433 BAC clones. To the high amplification occurrence and complex distri- determine whether any association between patterns of bution within chromosomes 1 and 12 in this group, DNA copy number alterations and tumor histotype amplification frequency plots were generated for these could be detected, tumors with several different diag- chromosomes (Figure 3a and b). The profile for noses were included in the investigation. chromosome 1 showed a distinct peak in 1p32, indicat- ing a recurrently amplified region of 1.18 Mb that contains four annotated genes, including JUN (Table 2). In 1q, three frequently amplified regions, all located Results within 1q23.2–1q24.3, were detected. The chromosome 12 profile revealed two narrow peaks of amplification The array CGH analysis revealed DNA copy number in 12q13.3–14.1 and 12q15, respectively, affected in alterations in all 13 soft tissue tumors and in all six bone more than 60% of the soft tissue tumors. The proximal tumors (Figure 1a, Table 1). Although several single- 0.42 Mb region contains 17 genes, including SAS and copy gains and losses of larger chromosomal segments CDK4, and the distal 0.75 Mb region comprises 16 were observed, the copy number changes were domi- genes, including MDM2. Other, less frequent, recurrent nated by genomic amplifications. As a lot of these amplifications in the soft tissue tumors were seen in demonstrated highly discontinuous patterns, large num- 3p11.1–12.1, 6q24.3–25.1 and 20q11.2–12.1 (Table 2). bers of very small amplicons were seen in the majority of The only chromosome showing overlapping amplifi- cases. In many instances, the amplification levels were cations in the bone tumors was chromosome 12. The higher than fivefold, including extreme cases in which amplification analysis revealed three small regions in more than 30-fold amplification were observed. Even 12p, all amplified in two of six cases (Table 2). The most though individual amplicons were dispersed throughout distal segment, located in 12p13.3, is 0.62 Mb in size and most of the genome, marked aggregations were observed contains seven genes, including CCND2, FGF6 and in specific chromosomes, mainly 1 and 12 (Figures 1 and FGF23.

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