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Sequence rearrangements and viral genomic state of Human Papillomavirus Type 16 Af-1 variants isolated from Ugandan Penile CarcinomasViral Oncology, AIDS Reference Center , Istituto Nazionale Tumori "Fond. G. Pascale", Naples - ITALY; irccsvir@unina.itAIMS: HPV-16 is the predominant HPV type found in malignancies of male and female lower genital tract. However only a small percentage of HPV-16 infected individuals develops a genital neoplasia suggesting that additional events both at cellular as well as at viral level are necessary in the progression to cancer, including genetic mutations/rearrangements of viral sequences involved in the oncogenic process. METHODS: The molecular status of HPV 16 genome was studied in 5 penile carcinoma samples using both Southern blot analysis and a PCR strategy for identifying disruption of the E2 gene. Identification and functional analysis of mutated and/or rearranged long control region (LCR, nt 7289-114) was performed by PCR amplification followed by sequence analysis, and CAT assay. RESULTS: In all 5 samples the virus was found randomly integrated into cellular genome with disruption of the E2 gene suggesting that, as described for cervical cancer, the integration of viral DNA in the host cell chromosome is a crucial event in the tumor progression. Two out of five samples showed further rearrangements of the enhancer region. The functional activity of LCR with Af-1 mutations and rearrangements was significantly higher than those driven by Af-1 or European (E) prototype LCRs. Furthermore, in the NIH3T3 focus formation assay, the transforming activity of E6 and E7 genes, driven by mutated or rearranged LCR, was 1.4 to 3.0-fold higher, respectively. CONCLUSIONS: These results indicate that rearrangements within LCR of HPV-16 isolates are not rare events and can play a major role in the pathogenesis of male genital carcinomas. For more information, contact irccsvir@unina.it Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Viral Oncogenesis. |
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