Abstract
Gene amplification is one of the common mechanisms that activate oncogenes. In this study, we used single nucleotide polymorphism array to analyze genome-wide DNA copy number alterations in 31 high-grade ovarian serous carcinomas, the most lethal gynecologic neoplastic disease in women. We identified an amplicon at 19p13.12 in 6 of 31 (19.5%) ovarian high-grade serous carcinomas. This amplification was validated by digital karyotyping, quantitative real-time PCR, and dual-color fluorescence in situ hybridization (FISH) analysis. Comprehensive mRNA expression analysis of all 34 genes within the minimal amplicon identified Notch3 as the gene that showed most significant overexpression in amplified tumors compared with nonamplified tumors. Furthermore, Notch3 DNA copy number is positively correlated with Notch3 protein expression based on parallel immunohistochemistry and FISH studies in 111 high-grade tumors. Inactivation of Notch3 by both gamma-secretase inhibitor and Notch3-specific small interfering RNA suppressed cell proliferation and induced apoptosis in the cell lines that overexpressed Notch3 but not in those with minimal amount of Notch3 expression. These results indicate that Notch3 is required for proliferation and survival of Notch3-amplified tumors and inactivation of Notch3 can be a potential therapeutic approach for ovarian carcinomas.
Highlights
Gene amplification is one of the key mechanisms in activating oncogenes in human cancer [1]
single nucleotide polymorphism (SNP) arrays were used to search for genome-wide DNA copy number alterations in 31 high-grade and 7 low-grade ovarian serous carcinomas
Amplification of the cyclin E1 locus was present in 10 of 31 (32.2%) samples and amplification of AKT2 locus in 9 of 31 (29%) samples. Both cyclin E1 and AKT2 have been previously reported as potential oncogenes that are frequently amplified in ovarian cancer
Summary
Gene amplification is one of the key mechanisms in activating oncogenes in human cancer [1]. We did SNP array analysis on 31 high-grade ovarian serous carcinomas purified One of the genes within this amplicon, Notch3, showed the most significant correlation between gene copy numbers and transcript expression in ovarian cancer, suggesting that Notch3 is a candidate oncogene in the chr19p13.12 amplicon.
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