Yan Taiqiang, Wunder Jay S, Gokgoz Nalan, Gill Mona, Eskandarian Sasha, Parkes Robert K, Bull Shelley B, Bell Robert S, Andrulis Irene L
Fred A. Litwin Centre for Cancer Genetics, Mount Sinai Hospital, and University Musculoskeletal Oncology Unit, Toronto, Ontario, Canada.
Cancer. 2007 May 1;109(9):1870-6. doi: 10.1002/cncr.22595.
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.
在高级别骨肉瘤中观察到多个定位于染色体17p11.2区域的基因发生扩增，包括COPS3。这些基因也被证明过度表达，可能参与骨肉瘤的肿瘤发生。COPS3编码COP9信号体的一个亚基，该信号体与P53肿瘤抑制因子的泛素化及最终降解有关。为了确定COPS3扩增、P53突变与骨肉瘤患者预后之间的关系，我们对一大群有高级别骨肉瘤且有长期临床随访的患者的肿瘤进行了检查。
采用定量实时聚合酶链反应（PCR）检测155例骨肉瘤中COPS3以及来自17p11.2扩增子的其他基因（NCOR1、TOM1L2和PMP22）的拷贝数变化，这些骨肉瘤来自一个前瞻性收集的肿瘤样本，并伴有相应的临床数据。进行单因素和多因素分析以评估各组之间生存率的差异。
在31%的骨肉瘤中检测到COPS3扩增，其与肿瘤体积大密切相关（P = 0.0009），但与诊断时的年龄、部位、性别和肿瘤坏死无关。在单因素分析中，COPS3扩增与转移时间缩短显著相关，估计风险比（HR）为1.61（95%置信区间[CI]，1.02 - 2.55）（对数秩检验，P = 0.042）。然而，在一个包含其他临床参数的先验多因素Cox模型中，COPS3扩增的HR降至1.32（95% CI，0.82 - 2.13，P = 0.25），主要是因为与肿瘤大小的强相关性。COPS3扩增和P53突变经常在同一肿瘤中发生，这表明在骨肉瘤中这些并非相互排斥的事件。虽然无统计学意义，但与单独有COPS3扩增或P53突变的患者相比，肿瘤同时出现这两种分子改变的患者更易发生转移。
COPS3可能是17p11.2扩增子的靶点。COPS3在骨肉瘤中可能起癌基因作用，拷贝数增加可能导致不良预后。
