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Cell Cycle Regulator Gene CDC5L, a Potential Target for 6P12-P21 Amplicon in Osteosarcoma

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Cell Cycle Regulator Gene CDC5L, a Potential Target for 6P12-P21 Amplicon in Osteosarcoma Cell Cycle Regulator Gene CDC5L, a Potential Target for 6p12-p21 Amplicon in Osteosarcoma Xin-Yan Lu,1,3 Yaojuan Lu,1 Yi-Jue Zhao,1 Kim Jaeweon,4 Jason Kang,4 Li Xiao-Nan,1 Gouqing Ge,1 Rene Meyer,1 Laszlo Perlaky,1 John Hicks,2 Murali Chintagumpala,1 Wei-Wen Cai,3 Marc Ladanyi,5 Richard Gorlick,6 Ching C. Lau,1 Debananda Pati,1 Michael Sheldon,1 and Pulivarthi H. Rao1 Departments of 1Pediatrics, 2Pathology, and 3Molecular and Human Genetics, Baylor College of Medicine; 4Spectral Genomics, Houston, Texas; 5Memorial Sloan Kettering Cancer Center, New York, New York; and 6The Children’s Hospital at Montefiore, Bronx, New York Abstract oncogenic activity. These results indicate that CDC5L, Osteosarcoma is a primary malignant tumor of bone a cell cycle regulator important for the G2-M transition, arising from primitive bone-forming mesenchymal cells is the most likely candidate oncogene for the and accounts for f60% of malignant bone tumors. 6p12-p21 amplicon found in osteosarcoma. Our comparative genomic hybridization (CGH) studies (Mol Cancer Res 2008;6(6):937–46) have identified frequent amplification at 6p12-p21, 12q13-q15, and 17p11.2 in osteosarcoma. Of these Introduction amplified regions, 6p12-p21 is particularly interesting Osteosarcomas are the most frequent malignant bone tumor because of its association with progression and poor in adults and children with a peak incidence during the second prognosis in patients with osteosarcoma. In an attempt decade of life (1). Sporadic human osteosarcomas often present to identify aberrantly expressed gene(s) mapping to with complex chromosomal rearrangements, deletions, and the 6p12-p21 amplicon, a region-specific array was amplifications, suggesting that genomic instability is linked generated using 108 overlapping BAC and P1 clones to the development of this tumor (2-8). Exposure to ionizing covering a 28.8-Mb region at 0.26-Mb intervals. Based on radiation, for example during radiotherapy of other cancers, is a array CGH analysis, the 6p amplicon was refined to high-risk factor for development of osteosarcoma at the irra- 7.9 Mb between the clones RP11-91E11 and RP1-244F2 diated site, further suggesting that DNA breakage and genomic and 10 amplified clones, with possible target genes, instability contribute to the development of this tumor (9). were identified. To study the expression pattern of the The identification of recurrent amplifications and deletions in target genes from the hotspot amplicon and known human osteogenic tumors may provide genetic evidence for candidate genes from 6p12-21, we did quantitative specific sequences that contribute to the malignant phenotype. reverse transcription-PCR analysis of MAPK14, MAPK13, CDKN1A, PIM1, MDGA1, BTB9, DNAH8, Recently, others and we have identified several chromosomal regions that are recurrently amplified in osteosarcoma by CCND3, PTK7, CDC5L, and RUNX2 on osteosarcoma chromosomal comparative genomic hybridization (CGH) and patient samples and seven cell lines. The combined array-based CGH (2-8, 10). Of these, amplification of 6p12-p21 array CGH and quantitative reverse transcription-PCR and 17p11.2appeared to be markers of an early genetic change in analysis identified amplification and overexpression osteosarcoma. The high frequency of copy number increases in of CDC5L, CCND3, and RUNX2. We screened these these regions suggests the presence of candidate oncogenes that three genes for protein expression by Western have yet to be identified. The 6p gain/amplicon has also been blotting and immunohistochemistry and detected reported in other tumor types, including bladder and pancreatic overexpression of CDC5L. Furthermore, we used an cancers, diffuse large B-cell lymphoma, and retinoblastoma in vivo assay to show that CDC5L possesses potential (11-14). However, the amplification in these tumors mapped to 6p22, which is telomeric to the amplicon found in osteosarcoma. Received 10/25/07; revised 2/12/08; accepted 2/27/08. The 6p12-p21 genomic region is particularly interesting because Grant support: National Childhood Cancer Foundation (Alex Lemonade Stand of its association with poor prognosis in patients with osteo- Funds; P.H. Rao), Dunn Foundation, Kleberg Foundation CA88126, CA114757 sarcoma.7 To date, no bona fide oncogene sequences have been (C.C. Lau), and National Cancer Institute grant 1RO1 CA109330 (D. Pati). The costs of publication of this article were defrayed in part by the payment of described in this region of the genome. Therefore, identification page charges. This article must therefore be hereby marked advertisement in of amplified gene(s) from the 6p12-p21 amplicon is extremely accordance with 18 U.S.C. Section 1734 solely to indicate this fact. important because it not only advances our understanding of Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). tumor initiation but also offers the potential for developing Current address for M. Sheldon: Department of Genetics, Rutgers University, Piscataway, New Jersey. Requests for reprints: Pulivarthi H. Rao, Texas Children’s Cancer Center, Baylor College of Medicine, 6621 Fannin Street, MC 3-3320, Houston, TX 77030. Phone: 832-824-4820; Fax: 832-825-4038. E-mail: [email protected] Copyright D 2008 American Association for Cancer Research. 7 P.H. Rao, et al. Gain of chromosome 7p and 8q23-q24 are associated with poor doi:10.1158/1541-7786.MCR-07-2115 prognosis in osteosarcoma, unpublished material. Mol Cancer Res 2008;6(6). June 2008 937 Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2008 American Association for Cancer Research. 938 Lu et al. nonsurgical treatments by targeting these molecules through Results gene therapy or antisense molecules. We recently did array Frequent Amplification of 6p12-p21 in Osteosarcoma CGH–based copy number analysis on primary osteosarcoma Using chromosomal CGH, we identified several recurrent tumors and identified a 9.4-Mb amplicon at 6p12-p21. high-level chromosomal amplifications at Xp11, 1q21, 4q12, To map the boundaries of the 6p12-p21 amplicon more 5p14-p15, 6p12-p21, 7p21-p22, 8q22-q23, 12q12-q15, 17p11, precisely, a region-specific CGH microarray was generated and 20p11.2 (7, 8). Of these, amplification of 6p12-p21 was not using 108 human BAC and PAC clones, which span a 28.8 Mb only present at high frequency but was also detected in all region of 6p in osteosarcoma. The analysis of genomic DNAs specimen types, including those from biopsy, definitive surgery, from osteosarcoma patients with 6p12-p21 amplification using and metastatic lesions, suggestive of an early event in the this region-specific array revealed a large amplification ‘‘field’’ pathogenesis of osteosarcoma. Our recent array CGH analysis covering 7.9 Mb between the clones RP11-91E11 and RP1- using 3-Mb arrays identified high-level amplification of the 244F2, and identified 10 amplified clones with possible target clones from 6p12-p21 in 12 of 48 (25%) of the cases (10). genes. Expression analysis of genes that map within these These findings strongly suggest the presence of potential amplified peaks identified several genes that are up-regulated in oncogene(s) in the 6p12-p21 region. We used Kaplan-Meier primary tumors and cell lines. The combined array CGH and analysis to determine the prognostic significance of the 6p12- quantitative reverse transcription PCR (qRT-PCR) analysis p21 amplification in 28 biopsies (11 good responders and 17 identified amplification and overexpression of CDC5L, poor responders). Amplification of 6p12-p21 was noted in 5 of CCND3,andRUNX2. Finally, we investigated whether 28 samples and patients with 6p12-p21 amplification displayed increased DNA copy number and overexpression of CCND3, a trend toward shorter event-free survival compared with CDC5L, and RUNX2 transcripts correlates with increased patients who did not have the amplification.7 protein levels in osteosarcoma cell lines and tissue microarray. Here, we present results from the detailed mapping of the 6p12- Fine Mapping of the 6p12-p21 Amplicon in Osteosarcoma p21 amplicon and expression analysis of genes that are To further define the 6p12-p21 amplicon, we applied a amplified in osteosarcoma. region-specific CGH array, composed of 108 contiguous BACs FIGURE 1. A. Partial 6p ideogram with a contig of BAC/P1 clones used to gener- ate region-specific array. Each bar represents a BAC/PAC clone. B. A representative re- gion-specific ratio profile of 6p12-p21 from case OS-204. In this experiment, tumor and normal DNA were labeled with Cy5 and Cy3, respectively. The dye reversal experiment was also done to avoid dye biases and hybridization artifacts. The mean ratios were plotted along the length of the chromosome. The clones on each chromo- some are arranged (pter to qter) based on University of California at Santa Cruz map- ping positions. Mol Cancer Res 2008;6(6). June 2008 Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2008 American Association for Cancer Research. CDC5L, Cell Cycle Regulatory Gene in Osteosarcoma 939 FIGURE 2. Amplicon mapping of 6p12-p21 in osteosarcoma. Log ratios of 10 BAC clones around the highly amplified region. All the clones are arranged (pter to qter) based on University of California at Santa Cruz mapping positions. and P1 clones covering a 28.8-Mb region at 0.26-Mb intervals, cells (NHOS) as a control reference. Only 3 of 11 genes, to the analysis of 26 osteosarcomas (Fig. 1A; see Supplemen- CCND3, CDC5L, and RUNX2, showed consistent overexpres- tary Data for array CGH). These 26 cases consist of 9 cases sion in all osteosarcoma patient samples studied (13 of 13). with no change on 6p, 5 cases with 6p gain, and 12cases with In contrast, MAPK14, MAPK13, CDKN1A, PIM1, MDGA1, 6p12-p21 amplification. A representative ratio profile of case BTB9, and PTK7 were underexpressed (Fig. 3B). Array CGH OS-204 showing the amplification of 6p12-p21 is shown in data is available for 4 of the 13 cases.
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