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  • Oncogenomics
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A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques

Oncogene volume 22, pages 3977–3984 (2003)Cite this article

Abstract

Persistent infections with high-risk human papillomaviruses (HPVs) induce dysplastic lesions of the lower genital tract. Some of these lesions eventually progress to invasive cancers, particularly of the uterine cervix. In many advanced preneoplastic cervical lesions and most derived carcinomas, HPV genomes are found to be integrated into the host cell chromosomes. Although HPV integration seems to play an important role in the progression of cervical dysplasia, the underlying mechanisms are still unclear. To investigate the pathogenic role of genomic integration of HPV genomes in greater detail, we analysed integration sites of HPV16 and 18 genomes in 21 anogenital precancerous and cancerous lesions using a ligation-mediated chain reaction (DIPS) and the recently described amplification of papilloma virus oncogene transcripts (APOT) assay. On the genomic level, only singular integration events were observed in individual neoplastic cell clones. At many integration sites, a short overlap between HPV and genomic sequences was observed, suggesting that the integration of HPV genomes is mediated by nonhomologous sequence-specific recombination. APOT analysis revealed that the majority of integrated HPV genomes was actively transcribed. These data suggest that in the progression of cervical preneoplasia to invasive carcinomas, integration of viral genomes occurs only at single or few chromosomal loci in a given cell clone. Disruption of cellular genes might support malignant transformation in rare cases; however, it is not a pathogenic prerequisite. The main function of HPV integration seems to be the stabilization of oncogene transcription.

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Acknowledgements

This work was supported by a grant of the ‘Deutsche Krebshilfe’ (10-1377-Ni I) to Magnus von Knebel Doeberitz. This article is dedicated to Haraldzurd Hausen on the occasion of his retirement as head of the German Cancer Research Center.

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Author notes

  1. Fjodor Kisseljov

    Present address: Institute of Carcinogenesis, Blokhin Russian Cancer Research Center, 115478, Moscow, Russia

  2. Jens Einenkel & Michael Hoeckel

    Present address: Department of Gynecology and Obstetrics, University of Leipzig, 04103, Leipzig, Germany

  3. Corina Ziegert and Nicolas Wentzensen: These authors contributed equally to this manuscript

Authors and Affiliations

  1. Department of Pathology, Institute of Molecular Pathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg, 69120, Germany

    Corina Ziegert, Nicolas Wentzensen, Svetlana Vinokurova & Magnus von Knebel Doeberitz

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  1. Corina Ziegert
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  2. Nicolas Wentzensen
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Correspondence to Magnus von Knebel Doeberitz.

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Ziegert, C., Wentzensen, N., Vinokurova, S. et al. A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques. Oncogene 22, 3977–3984 (2003). https://doi.org/10.1038/sj.onc.1206629

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