DNA Aneuploidy and Integration of Human Papillomavirus Type 16 E6/E7 Oncogenes in Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix Uteri

Clinical Cancer Research - Tập 10 Số 9 - Trang 3059-3063 - 2004
Peter Melsheimer1, Svetlana Vinokurova2, Nicolas Wentzensen2, G. Bastert3,4, Magnus von Knebel Doeberitz2,5
1Department of Obstetrics, Gynecology and Gynecological Oncology, Medical School, University of Heidelberg, Heidelberg, Germany.
22Institute of Molecular Pathology, Department of Pathology, University of Heidelberg, Heidelberg, Germany
31Department of Obstetrics, Gynecology and Gynecological Oncology, Medical School, and
4University of Heidelberg
5Translational Cancer Research

Tóm tắt

Abstract Purpose: Increasingly deregulated expression of the E6-E7 oncogenes of high-risk human papillomaviruses (HR-HPVs) has been identified as the major transforming factor in the pathogenesis of cervical dysplasia and derived cancers. The expression of these genes in epithelial stem cells first results in chromosomal instability and induces chromosomal aneuploidy. It is speculated that this subsequently favors integration of HR-HPV genomes into cellular chromosomes. This in turn leads to expression of viral cellular fusion transcripts and further enhanced expression of the E6-E7 oncoproteins. Chromosomal instability and aneuploidization thus seems to precede and favor integration of HR-HPV genomes. Experimental Design: To prove this sequential concept, we analyzed here the sequence of events of DNA aneuploidization and integration in a series of HPV-16-positive cervical dysplastic lesions and carcinomas. Eighty-five punch biopsies of HPV-16-positive cervical lesions (20 CIN1/2, 50 CIN3, and 15 CxCa) were analyzed for DNA ploidy by DNA flow cytometry and for integration of HPV E6/E7 oncogenes using the amplification of papillomavirus oncogene transcripts assay, a reverse transcription-PCR method to detect integrate-derived human papillomavirus oncogene transcripts. Results: DNA aneuploidy and viral genome integration were both associated with increasing dysplasia (P < 0.001, χ2 test for trend). In addition, DNA aneuploidy was associated with increased viral integration (P < 0.01, Fisher’s exact test). Nineteen of 20 (95%) lesions with integrated viral genomes had aneuploid cell lines; however, only 19 of 32 (59%) lesions with aneuploid cell lines had integrated viral genomes. Conclusions: These data support the hypothesis that aneuploidization precedes integration of HR-HPV genomes in the progression of cervical dysplasia. Accordingly, deregulated viral oncogene expression appears to result first in chromosomal instability and aneuploidization and is subsequently followed by integration of HR-HPV genomes in the affected cell clones.

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Clinical Cancer Research

Tập 10 Số 9

3059-3063

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