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COPS3 amplification and clinical outcome in osteosarcoma
Article first published online: 15 MAR 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 9, pages 1870–1876, 1 May 2007
How to Cite
Yan, T., Wunder, J. S., Gokgoz, N., Gill, M., Eskandarian, S., Parkes, R. K., Bull, S. B., Bell, R. S. and Andrulis, I. L. (2007), COPS3 amplification and clinical outcome in osteosarcoma. Cancer, 109: 1870–1876. doi: 10.1002/cncr.22595
- Issue published online: 18 APR 2007
- Article first published online: 15 MAR 2007
- Manuscript Accepted: 16 JAN 2007
- Manuscript Revised: 10 JAN 2007
- Manuscript Received: 14 NOV 2006
- Ontario Cancer Research Network
- Canadian Institutes of Health Research
- S.B.B. holds a Senior Investigator Award from the Canadian Institutes of Health Research
- gene amplification;
Amplification of several genes that map to a region of chromosome 17p11.2, including COPS3, was observed in high-grade osteosarcoma. These genes were also shown to be overexpressed and may be involved in osteosarcoma tumorigenesis. COPS3 encodes a subunit of the COP9 signalosome implicated in the ubiquitination and ultimately degradation of the P53 tumor suppressor. To determine the relation between COPS3 amplification, P53 mutation, and patient outcome in osteosarcoma, tumors from a large cohort of patients with high-grade osteosarcoma and long-term clinical follow-up were examined.
Quantitative real-time polymerase chain reaction (PCR) was performed to detect copy number changes for COPS3, as well as additional genes (NCOR1, TOM1L2, and PMP22) from the 17p11.2 amplicon, in 155 osteosarcomas from a prospective collection of tumors with corresponding clinical data. Univariate and multivariate analyses were performed to assess differences in survival between groups.
Amplification of COPS3, detected in 31% of the osteosarcomas, was strongly associated with large tumor size (P = .0009), but was not associated with age at diagnosis, site, sex, and tumor necrosis. COPS3 amplification was significantly correlated with a shorter time to metastasis with an estimated hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.02–2.55) in univariate analysis (log-rank test, P = .042). However, in an a priori multivariate Cox model including the other clinical parameters, the HR for COPS3 amplification decreased to 1.32 (95% CI, 0.82–2.13, P = .25), mainly due to the strong correlation with tumor size. COPS3 amplification and P53 mutation frequently occurred in the same tumors, suggesting that these are not mutually exclusive events in osteosarcoma. Although not statistically significant, patients whose tumors exhibited both molecular alterations tended to be more likely to develop metastasis compared with patients with either COPS3 amplification or P53 mutation alone.
COPS3 is the likely target of the 17p11.2 amplicon. COPS3 may function as an oncogene in osteosarcoma, and an increased copy number may lead to an unfavorable prognosis. Cancer 2007. © 2007 American Cancer Society.