COPS3 amplification and clinical outcome in osteosarcoma.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Yan
Taiqiang
T
Fred A. Litwin Centre for Cancer Genetics, Mount Sinai Hospital, and University Musculoskeletal Oncology Unit, Toronto, Ontario, Canada.
Wunder
Jay S
JS
Gokgoz
Nalan
N
Gill
Mona
M
Eskandarian
Sasha
S
Parkes
Robert K
RK
Bull
Shelley B
SB
Bell
Robert S
RS
Andrulis
Irene L
IL
D000293:Adolescent; D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000075686:COP9 Signalosome Complex; D002675:Child, Preschool; D005260:Female; D005784:Gene Amplification; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009185:Myelin Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D056971:Nuclear Receptor Co-Repressor 1; D012516:Osteosarcoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C477661:COPS3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009185:Myelin Proteins; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; C073687:PMP22 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C120296:TOM1 protein, human; D016159:Tumor Suppressor Protein p53; D000075686:COP9 Signalosome Complex