This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koopman, L. A. Articles by Jan Fleuren, G. Search for Related Content PubMed PubMed Citation Articles by Koopman, L. A. Articles by Jan Fleuren, G.

Recurrent Integration of Human Papillomaviruses 16, 45, and 67 Near Translocation Breakpoints in New Cervical Cancer Cell Lines¹

Departments of Pathology [L. A. K., J. D. H. v. E., E. S., G. J. F.] and Gynecology [G. G. K], Leiden University Medical Center, and Laboratory for Cytochemistry and Cytometry, Department of Molecular Cell Biology, Leiden University Medical Center, [K. S., V. B., H. T.], Leiden, The Netherlands

Progressive chromosomal changes and integration of human papillomavirus (HPV) sequences mark the development of invasive cervical cancer. Chromosomal localization of HPV integration is essential to the study of genomic regions involved in HPV-induced pathogenesis. Yet, the available information about HPV integration loci is still limited, especially with respect to different HPV types. We have established cell lines from five cervical cancers with HPV-16, HPV-45, and HPV-67. We have determined HPV integration sites and karyotype abnormalities by using the multicolor combined binary ratio-fluorescence in situ hybridization method (Tanke et al.) with 24 chromosome-specific paints in combination with full-length HPV DNA probes.

All cell lines were cytogenetically abnormal, and exhibited numerical and structural chromosomal deviations. HPV sequences were integrated at various (segments of) chromosomes. Duplicate integration sites were seen in all multiploid cell lines, suggesting that viral integration had preceded chromosomal endoreduplication. HPV-16 was found near the t(3p14.1–14.3;14) breakpoint in cervical squamous cell carcinoma (CSCC)-7 and mainly in episomal form in CSCC-1. HPV-45 was integrated near 3q26–29 in cervical (adeno or adenosquamous) carcinoma (CC)-8 and near 1q21–23 as well as near the t(1q21;22q13) breakpoint in CC-10A and CC-10B variant lines. HPV-67 was localized near the breakpoint of t(3p23–26;13q22–31) in CC-11. Southern blot analysis showed that, except for CSCC-1, the physical state of HPV in the cell lines was the same as in the original tumor lesions.

This set of six cervical cancer cell lines included three lines with HPV-45, a major non-Western high-risk HPV type, the first reported HPV-67-positive cell line, and two cell lines with integrated and episomal HPV-16 DNA, respectively. The novel combined binary ratio-fluorescence in situ hybridization technique enabled us to simultaneously map chromosomal rearrangements and HPV integration sites, thereby revealing recurrent integration near translocation junctions for all of these HPV types in the cell lines from three of the five primary tumors. The detection of multiple HPV integration sites at rearranged chromosomes at such high frequency in cervical cancer-derived cells may reflect events that are relevant to the development of cervical cancer.

This article has been cited by other articles:

				I. Kraus, C. Driesch, S. Vinokurova, E. Hovig, A. Schneider, M. von Knebel Doeberitz, and M. Durst The Majority of Viral-Cellular Fusion Transcripts in Cervical Carcinomas Cotranscribe Cellular Sequences of Known or Predicted Genes Cancer Res., April 1, 2008; 68(7): 2514 - 2522. [Abstract] [Full Text] [PDF]

				J. N. Kloth, G. J. Fleuren, J. Oosting, R. X. de Menezes, P. H.C. Eilers, G. G. Kenter, and A. Gorter Substantial changes in gene expression of Wnt, MAPK and TNF{alpha} pathways induced by TGF-{beta}1 in cervical cancer cell lines Carcinogenesis, September 1, 2005; 26(9): 1493 - 1502. [Abstract] [Full Text] [PDF]

				N. Wentzensen, S. Vinokurova, and M. v. K. Doeberitz Systematic Review of Genomic Integration Sites of Human Papillomavirus Genomes in Epithelial Dysplasia and Invasive Cancer of the Female Lower Genital Tract Cancer Res., June 1, 2004; 64(11): 3878 - 3884. [Abstract] [Full Text] [PDF]

				P. Peitsaro, S. Hietanen, B. Johansson, T. Lakkala, and S. Syrjanen Single copy heterozygote integration of HPV 33 in chromosomal band 5p14 is found in an epithelial cell clone with selective growth advantage Carcinogenesis, June 1, 2002; 23(6): 1057 - 1064. [Abstract] [Full Text] [PDF]

				M. H. Einstein, Y. Cruz, M. K. El-Awady, N. C. Popescu, J. A. DiPaolo, M. van Ranst, A. S. Kadish, S. Romney, C. D. Runowicz, and R. D. Burk Utilization of the Human Genome Sequence Localizes Human Papillomavirus Type 16 DNA Integrated into the TNFAIP2 Gene in a Fatal Cervical Cancer from a 39-Year-Old Woman Clin. Cancer Res., February 1, 2002; 8(2): 549 - 554. [Abstract] [Full Text] [PDF]

				K. Szuhai, E. Sandhaus, S. M. Kolkman-Uljee, M. Lemaitre, J.-C. Truffert, R. W. Dirks, H. J. Tanke, G. J. Fleuren, E. Schuuring, and A. K. Raap A Novel Strategy for Human Papillomavirus Detection and Genotyping with SybrGreen and Molecular Beacon Polymerase Chain Reaction Am. J. Pathol., November 1, 2001; 159(5): 1651 - 1660. [Abstract] [Full Text] [PDF]

				X. Sastre-Garau, M. Favre, J. Couturier, and G. Orth Distinct patterns of alteration of myc genes associated with integration of human papillomavirus type 16 or type 45 DNA in two genital tumours J. Gen. Virol., August 1, 2000; 81(8): 1983 - 1993. [Abstract] [Full Text]

				L. A. Koopman, W. E. Corver, A. R. van der Slik, M. J. Giphart, and G. J. Fleuren Multiple Genetic Alterations Cause Frequent and Heterogeneous Human Histocompatibility Leukocyte Antigen Class I Loss in Cervical Cancer J. Exp. Med., March 20, 2000; 191(6): 961 - 976. [Abstract] [Full Text] [PDF]