Identification and Characterization of Genomic Amplifications in Ovarian Serous Carcinoma

摘要

The purpose of this proposed study is to apply genome-wide technologies to analyze ovarian cancer genome and transcriptome. We have accomplished all the proposed tasks as stated in the original grant. They include generating digital karyotyping libraries from ovarian carcinomas and perform transcirptome analysis in each amplicon. This effort leads us to identify at least two novel candidate oncogenes, Rsf1 and Notch3, which were up- regulated in both genomic DNA and transcript levels in ovarian cancer. In a large-scale FISH analysis, Rsf1 gene amplification was found to be correlated with a worse disease outcome. Furthermore, Rsf1 overexpression was found to lead to taxol resistance, which may explain why patient with Rsf1 amplification has a shorter overall survival. Because of recent advances in technology refinement, we have found that high density SNP array can provide a similar performance as digital karyotyping. Due to its lower cost, we are able to perform SNP array on more than 80 affinity purified ovarian serous tumors, initially with 10K platform and later on with 250K array platform. Our results demonstrated that CCNE1, Notch3, Rsf1, AKT2 and PIK3CA were among the most frequently amplified loci in high-grade ovarian serous carcinomas. In addition, we have further characterized the biological functions of the two commonly amplified genes, Notch3 and Rsf1. Our study is the first comprehensive analysis of the detailed copy number profiles in ovarian cancerors. The results from this study shall provide a new insight into how amplified or deleted genes contribute to survival and growth advantages in ovarian cancer cells.