Identification of Novel Candidate Oncogenes in Chromosome Region 17p11.2-p12 in Human Osteosarcoma

Abstract

Osteosarcoma is the most common primary malignancy of bone. The tumours are characterized by high genomic instability, including the occurrence of multiple regions of amplifications and deletions. Chromosome region 17p11.2–p12 is amplified in about 25% of cases. In previous studies, COPS3 and PMP22 have been identified as candidate oncogenes in this region. Considering the complexity and variation of the amplification profiles for this segment, the involvement of additional causative oncogenes is to be expected. The aim of the present investigation is to identify novel candidate oncogenes in 17p11.2–p12. We selected 26 of in total 85 osteosarcoma samples (31%) with amplification events in 17p11.2–p12, using quantitative PCR for 8 marker genes. These were subjected to high-resolution SNP array analysis and subsequent GISTIC analysis to identify the most significantly amplified regions. Two major amplification peaks were found in the 17p11.2–p12 region. Overexpression as a consequence of gene amplification is a major mechanism for oncogene activation in tumours. Therefore, to identify the causative oncogenes, we next determined expression levels of all genes within the two segments using expression array data that could be generated for 20 of the selected samples. We identified 11 genes that were overexpressed through amplification in at least 50% of cases. Nine of these, c17orf39, RICH2, c17orf45, TOP3A, COPS3, SHMT1, PRPSAP2, PMP22, and RASD1, demonstrated a significant association between copy number and expression level. We conclude that these genes, including COPS3 and PMP22, are candidate oncogenes in 17p11.2–p12 of importance in osteosarcoma tumourigenesis.

Integrated analysis of gene expression and genomic aberration data in osteosarcoma (OS)

“…28 And it was reported that COPS3 is a candidate oncogene of importance in OS tumorigenesis. 31 Functional studies will be needed to test for their oncogenic potential.…”

Fine mapping of bone structure and strength QTLs in heterogeneous stock rat

“…Among all the genes detected underlying QTL on chromosome 10, several genes have previously shown to play important functions in bone growth and remodeling (Table 2). Cops3 is an oncogene residing in the human chromosomal region 17p11.2-p12 - the copy number and expression level of Cops3 was significantly associated with the development of osteosarcoma, the most common primary malignancy of bone [29,30]. Drg2 , a GTP binding protein, overexpression of which in transgenic mice leads to increased number and activity of osteoclasts and bone loss [31].…”

“…Mutation of Rai leads to craniofacial and skeletal anomalies (short extremities) in Smith-Magenis syndrome [32]. Both the copy number and expression level of Rasd1 were significantly associated with the development of osteosarcoma [29]. In addition, using an integrative genetics approach, Rasd1 was identified as a strong candidate gene for a BMD QTL in mice [34].…”

“…Srebf1 activates genes that regulate lipid biosynthesis, and polymorphism in this gene was found to be associated with a higher risk of osteonecrosis of the femoral head in the Korean population [35]. Shmt1 and Top3a are oncogenes and contribute to the development of osteosarcoma [29,38]. …”

Review of the GAS3 Family of Proteins and their Relevance to Cancer

“…Amplification of the chromosome 17p11.2 region and PMP22 expression have been associated with human osteosarcoma and glioblastoma in tissue and cell lines. 31–36 Moreover, in vitro and in vivo data suggest PMP22 may play a role in the neoplastic transformation process of the normal pancreas to premalignant lesions to pancreatic cancer. 37 This varied expression in different tumor types suggests that the role of PMP22 in growth arrest and differentiation may be cell and tissue specific.…”