Gain of chromosome 5p is seen in up to 75% of advanced cervical squamous cell carcinomas (SCC), although the genes responsible for the selective advantage provided by this abnormality are poorly understood. In the W12 cervical carcinogenesis model, we observed that 5p gain was rapidly selected over ~15 population doublings and was associated with the acquisition of a growth advantage and invasiveness. The most significantly upregulated transcript following 5p gain was the microRNA (miRNA)processor Drosha. In clinically progressed cervical SCC, Drosha copy-number gain was seen in 21/36 clinical samples and 8/10 cell lines and there was a significant association between Drosha transcript levels and copy-number gain. Other genes in the miRNA processing pathway, DGCR8, XPO5 and Dicer, showed infrequent copy-number gain and over-expression. Drosha copy-number and expression were not elevated in premalignant cervical squamous intraepithelial lesions. Importantly, global miRNA profiling showed that Drosha over-expression in cervical SCC appears to be of functional significance. In cultured cervical keratinocytes, a large subset of 48 miRNAs was differentially expressed according to Drosha status. Hierarchical clustering based on this subset showed that both cervical SCC cell lines and clinical specimens grouped according to Drosha over-expression. Many miRNAs deregulated in samples with Drosha over-expression are associated with carcinogenesis in other tissues, suggesting that they regulate fundamental processes in neoplastic progression. Our evidence suggests that copy-number driven over-expression of Drosha and consequent changes in miRNA profiles are likely to be important contributors to the selective advantage provided by 5p gain in cervical neoplastic progression.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA