Abstract
Abstract Integration of the viral DNA in the cellular genome has been suggested to be critical in carcinogenic progression of HPV-associated cervical neoplasia. This event can be accompanied by disruption of the open reading frame (ORF) encoding the E2 repressor, thus leading to transcriptional up-regulation of the E6 and E7 viral oncogenes. At this stage, it is unclear whether disruption of the E2 ORF is mandatory for carcinogenic progression. We measured E2 RNA and protein expression in clinical samples of various grades of HPV16-associated cervical neoplasia and compared it with the status of the viral genome. RNA extracted from paraffin embedded tissues was hybridized to specific probes and quantified by the NanoString technology. Protein expression was appreciated by immunohistochemistry and the status of viral DNA was determined by in situ hybridization, all performed on serial sections of the same samples. E2 protein was found highly expressed in CIN2 lesions where the HPV DNA was highly replicating, while it was decreased in more advanced grade lesions where replication is decreased or lost (CIN3 and SCC). Our data demonstrate that integration of the viral DNA in the cellular genome is always accompanied by drastic reduction of expression of the E2 protein, even when the E2 ORF is not disrupted by integration. The viral genes appear differentially expressed during progression as transcription of the HPV16 E6/E7 oncogenes, only when compared to E2-E4, is significantly higher in high grade lesions than in CIN2. In addition, transcription of 400 cellular genes of the cell cycle and immune-response were also studied in 20 clinical samples that show modulation during progression. We will discuss the establishment of a transcriptional signature for progression in cervical cancer and the role of local immune response in the fate of cervical lesions associated with HPV16. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-268. doi:1538-7445.AM2012-LB-268
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