Integration of human papillomavirus type 16 into cellular DNA of cervical carcinoma: Preferential deletion of the E2 gene and invariable retention of the long control region and the E6/E7 open reading frames

Choo, Kong‐Bung; Pan, Chao-Chih; Han, Shou‐Hwa

doi:10.1016/0042-6822(87)90195-4

Cited by 200 publications

(136 citation statements)

References 17 publications

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“…Firstly, organotypic cultures demonstrated that the growth advantage acquired by W12 in monolayer culture after integration was associated with progression from a low-grade epithelium to a high-grade epithelium with microinvasive properties. Secondly, integration caused partial deletion of the E2 ORF, as is commonly observed in vivo and in vitro (11,47), and occurred in the same chromosomal location as the common fragile site FRA5E, further supporting the evidence for preferential integration of HR-HPVs at or near common fragile sites (30,32,48). Thirdly, a number of the host genomic changes acquired by W12 during selection in vitro have also been described to occur during cervical carcinogenesis in vivo.…”

Section: Discussionmentioning

confidence: 57%

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

et al. 2004

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Whereas two key steps in cervical carcinogenesis are integration of high-risk human papillomavirus (HR-HPV) and acquisition of an unstable host genome, the temporal association between these events is poorly understood. Chromosomal instability is induced when HR-HPV E7 oncoprotein is overexpressed from heterologous promoters in vitro. However, it is not known whether such events occur at the "physiologically" elevated levels of E7 produced by deregulation of the homologous HR-HPV promoter after integration. Indeed, an alternative possibility is that integration in vivo is favored in an already unstable host genome. We have addressed these issues using the unique human papillomavirus (HPV) 16-containing cervical keratinocyte cell line W12, which was derived from a low-grade squamous intraepithelial lesion and thus acquired HPV16 by "natural" infection. Whereas W12 at low passage contains HPV16 episomes only, long-term culture results in the emergence of cells containing integrated HPV16 only. We show that integration of HPV16 in W12 is associated with 3 deletion of the E2 transcriptional repressor, resulting in deregulation of the homologous promoter of the integrant and an increase in E7 protein levels. We further demonstrate that high-level chromosomal instability develops in W12 only after integration and that the forms of instability observed correlate with the physical state of HPV16 DNA and the level of E7 protein. Whereas intermediate E7 levels are associated with numerical chromosomal abnormalities, maximal levels are associated with both numerical and structural aberrations. HR-HPV integration is likely to be a critical event in cervical carcinogenesis, preceding the development of chromosomal abnormalities that drive malignant progression.

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Section: Discussionmentioning

confidence: 57%

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

et al. 2004

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“…However, tumors have been reported that contain more than one integration site (Choo et al, 1987;Luft et al, 2001). In this study, 4/ 26 tumors were found to contain multiple integration sites ( Figure 1).…”

Section: Multiple Hpv16 Integrations Were Detected In Some Tumorsmentioning

confidence: 80%

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

Thorland¹,

Myers²,

et al. 2003

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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 (Po0.001). 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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“…In contrast, premalignant and benign cervical lesions predominantly contain episomal HPV DNA (Diirst et al, 1985;Lehn et al, 1988;Cullen et al, 1991). HPV DNA integration regularly occurs within the viral El/E2 region (Schwarz et al, 1985;Baker et al, 1987;Choo et al, 1987;Shirasawa et al, 1989), thereby disrupting E2 expression. Since the HPV E20RF encodes transcriptional modulator proteins Cripe et al, 1987;Bernard et al, 1989;Romanczuk et al, 1990), it has been suggested that integration-mediated disruption of E2 expression would trigger uncontrolled expression of the transforming genes E6 and E7.…”

Section: Introductionmentioning

confidence: 99%

Human papillomavirus (HPV) type 16 and 33 E6/E7 region transcripts in tonsillar carcinomas can originate from integrated and episomal HPV DNA

Snijders¹,

Meijer²,

Brule³

et al. 1992

Journal of General Virology

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This study was undertaken to determine whether human papillomavirus (HPV) E6/E7 gene transcription in tonsillar carcinomas is correlated with viral DNA integration. Therefore, tonsillar carcinomas containing HPV-16 (n = 2) and HPV-33 (n = 2) DNA were analysed for the viral physical state and transcription of the E6/E7 region. Southern blot analysis, DNA polymerase chain reaction (PCR) and, eventually, twodimensional gel electrophoresis revealed indications for the presence of only episomal DNA in the HPV-16-containing biopsies and only integrated DNA in one HPV-33-containing biopsy. The second HPV-33-containing carcinoma, from which one biopsy and two resected tumour specimens were analysed, showed a rather complex physical state profile. The biopsy of this tumour contained only episomal DNA, one resected tumour part contained only integrated DNA and the remaining tumour part contained both integrated and episomal HPV-33 DNA. Independent of the viral physical state, all biopsies and resected tumour parts tested showed the presence of E6/E7 transcripts as determined by RNA PCR. The results indicate that E6/E7 transcripts in tonsillar carcinomas can originate from integrated as well as episomal HPV DNA.

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Integration of human papillomavirus type 16 into cellular DNA of cervical carcinoma: Preferential deletion of the E2 gene and invariable retention of the long control region and the E6/E7 open reading frames

Cited by 200 publications

References 17 publications

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

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

Human papillomavirus (HPV) type 16 and 33 E6/E7 region transcripts in tonsillar carcinomas can originate from integrated and episomal HPV DNA

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