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Common fragile sites are preferential targets for HPV16 integrations in cervical tumors

Oncogene volume 22, pages 1225–1237 (2003)Cite this article

Abstract

The development of cervical cancer is highly associated with human papillomavirus (HPV) infection. HPV integration into the genome of infected cervical cells is temporally associated with the acquisition of the malignant phenotype. A relationship between the sites of HPV integration in cervical cancer and the position of the common fragile sites (CFSs) has been observed at both the cytogenetic and molecular levels. To further explore this relationship at the molecular level, we used RS–PCR to rapidly isolate cellular sequences flanking the sites of HPV16 integration in 26 primary cervical tumors. Human bacterial artificial chromosome clones were isolated based on these flanking sequences and used as probes for fluorescence in situ hybridization on aphidicolin-stimulated metaphases. Our data demonstrate that 11/23 HPV16 integrations in cervical tumors occurred within CFSs (P<0.001). In addition, we show that deletions and complex rearrangements frequently occur in the cellular sequences targeted by the integrations and that integrations cluster in FRA13C (13q22), FRA3B (3p14.2), and FRA17B (17q23). Finally, our data suggest that cellular genes, such as Notch 1, are disrupted by the HPV16 integrations, which may contribute to the malignant phenotype.

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Acknowledgements

We thank Drs Stephen Iturria and Stacy Denison for their discussions on our statistical methods and Renee McGovern for help with the acquisition and typing of samples. This work was supported by NIH Grant CA48031 and DIS was supported by Department of Defense Grant DAMD 17-99-1-9504.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology Mayo clinic, Rochester, 55905, MN, USA

    Erik C Thorland

  2. Department of Tumor Biology, Mayo clinic, Rochester, 55905, MN, USA

    Shannon L Myers

  3. Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, 55905, MN, USA

    Bobbie S Gostout

  4. Department of Experimental Pathology, Mayo Clinic, Rochester, 55905, MN, USA

    David I Smith

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  1. Erik C Thorland
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Correspondence to David I Smith.

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Thorland, E., Myers, S., Gostout, B. et al. Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. Oncogene 22, 1225–1237 (2003). https://doi.org/10.1038/sj.onc.1206170

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