Systematic Review of Genomic Integration Sites of Human Papillomavirus Genomes in Epithelial Dysplasia and Invasive Cancer of the Female Lower Genital Tract

Wentzensen, Nicolas; Vinokurova, Svetlana; Doeberitz, Magnus von Knebel

doi:10.1158/0008-5472.can-04-0009

Cited by 402 publications

(369 citation statements)

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“…Up to 181 different sites corresponding to 243 cases have been observed (Brink et al, 2002;Klimov et al, 2002;Wentzensen et al, 2004;Kraus et al, 2005;and our unpublished results). In spite of this scattering, it is remarkable that the chromosome band 8q24, to which MYC maps, is the most recurrent site for insertion of HPV DNA, as it is found in 10.7% (26/243) of the all cases (Du¨rst et al, 1987;Popescu et al, 1987;Couturier et al, 1991;Hori et al, 1991;Brink et al, 2002;Wentzensen et al, 2002;Ferber et al, 2003b;Ziegert et al, 2003;Kraus et al, 2005).…”

Section: Discussionsupporting

confidence: 64%

“…These data suggest that MYC activation could be secondary to the insertion of HPV DNA sequences at the MYC locus. Although a large diversity of integration sites has been reported (Wentzensen et al, 2004), MYC chromosome region is the most recurrent localization for HPV insertion, found in about 10% of genital neoplasias, observed in chromosome band 8q24 by fluorescence in situ hybridization (FISH) (Du¨rst et al, 1987;Couturier et al, 1991;Hori et al, 1991;Brink et al, 2002) or at the MYC locus by DNA/RNA analysis (Wentzensen et al, 2002;Ferber et al, 2003b;Ziegert et al, 2003;Kraus et al, 2005). However, despite this recurrence, no evidence of MYC overexpression directly associated with the insertion of HPV DNA at the MYC locus has been shown so far.…”

Section: Introductionmentioning

confidence: 99%

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MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

et al. 2006

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To determine whether integration of human papillomavirus (HPV) DNA sequences could lead to the deregulation of genes implied in oncogenesis, we analysed the HPV integration sites in a series of nine cell lines derived from invasive genital carcinomas. Using in situ hybridization, HPV16 or 18 sequences were found at chromosome band 8q24, the localization of MYC, in IC1, IC2, IC3, IC6 and CAC-1 cells and at other sites in IC4, IC5, IC7 and IC8 cells. We then localized viral sequences at the molecular level and searched for alterations of MYC structure and expression in these cells. MYC genomic status and viral integration sites were also analysed in primary tumors from which IC1, IC2, IC3 and IC6 cells were derived. In IC1, IC2 and CAC-1 cells, HPV DNA was located within 58 kb of MYC, downstream, upstream, or within MYC. In IC3 and IC6 cells, HPV DNA was located 400-500 kb upstream of MYC. Amplification studies showed that, in IC1, IC2 and IC3, viral and MYC sequences were coamplified in an amplicon between less than 50 and 800 kb in size. MYC amplification was also observed in primary tumors, indicating that this genetic alteration, together with viral insertion at the MYC locus, had already taken place in vivo. MYC was not amplified in the other cell lines. MYC mRNA and protein overexpression was observed in the five cell lines in which the HPV DNA was inserted close to the MYC locus, but in none of the lines where the insertion had occurred at other sites. MYC activation, triggered by the insertion of HPV DNA sequences, can be an important genetic event in cervical oncogenesis.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

et al. 2006

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“…On the other hand, Melsheimer et al (2004) have shown that in CIN and cervical carcinomas aneuploidization precedes integration of HPV DNA in the progression of cervical dysplasia. However, irrespective of a temporal association between integration and genetic instability, the current concept of cervical carcinogenesis suggests that integration provides the cell with a selective growth advantage (Duensing and Munger, 2004;Wentzensen et al, 2004). Several in vitro studies indicate that this growth advantage results from an enhanced expression of HPV E6 and E7.…”

Section: Figurementioning

confidence: 99%

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

et al. 2007

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Virus integration into the host genome is a characteristic step during cervical carcinogenesis. Experimental data provide evidence that integration could result in increased levels of oncogene (E6/E7) transcripts. This is the first study in which the level of viral transcripts is correlated to the physical state of the viral genome in cervical intraepithelial neoplasia (CIN) and cervical carcinomas (CxCa). Using the APOT-assay integrate-derived transcripts only were detected in 3/28 (11%) CIN and in 28/55 (51%) carcinomas, respectively. The remaining biopsies contained either episome-derived transcripts only or both mRNA species. SybrGreen real time reverse transcriptase-PCR assays were used to quantify viral gene expression for (i) all transcripts initiated from p97, (ii) full-length E6, (iii) E6*I and (iv) E5 transcripts. E6/E7 transcript levels showed a broad distribution but similar median values irrespective of histopathological grading and physical state of the viral genome. Biopsies with integrate-derived transcripts only generally lacked E5-specific mRNA. Our data do not support the hypothesis that HPV integration invariably results in high levels of oncogene transcripts. Instead, constitutive expression of oncogene transcripts rather than the level of expression appears to be decisive for transformation and the maintenance of the malignant phenotype.

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“…The integration process generally results in disruption of the HPV E1/E2 DNA region, leading to failure of the vegetative viral DNA replication process and constitutive expression of the E6 and E7 genes following the loss of transcriptional repression by E2. 16,17 Mutations in the p53 protein, with concomitant loss of wildtype p53 function, are found in over half of all human tumours. 18 The p53 protein is a powerful transcription factor (affecting 300 promoter elements within the genome) that can orchestrate cellcycle arrest and/or apoptosis under appropriate situations of cell stress.…”

mentioning

confidence: 99%

Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes

Gray¹,

Bjelogrlić²,

Appleyard³

et al. 2007

Intl Journal of Cancer

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Human papillomavirus (HPV) infection is strongly associated with the development of anogenital neoplasia, particularly cervical cancer. It has been estimated that 99.7% of all cervical carcinomas are attributable to infection with HPV, and types 16 and 18 account for the vast majority of such cases. Both of these Ôhigh riskÕ HPV types encode the oncoproteins E6 and E7, which exert multiple effects on many proteins involved in cell-cycle regulation, including p53. The nuclear export protein inhibitor leptomycin B (LMB) has been shown to cause the nuclear sequestration of p53 in cervical carcinoma cells. We demonstrate that LMB induces apoptosis selectively at nanomolar concentrations in primary human keratinocytes (PHKs) expressing HPV oncogenes. Both monolayer and organotypic raft cultures of transduced PHKs were highly susceptible to treatment with LMB. By contrast, although LMB stimulated p53 accumulation in normal PHKs, no significant induction of apoptosis was detected on Western blots or immunostained monolayer/raft cells, or following pulsed exposure to the drug. Furthermore, topical application of lM concentrations of LMB to mouse skin was non-toxic. These data suggest that the topical application of LMB to HPV-infected intra-epithelial lesions may represent a specific and effective therapeutic strategy against HPV-associated anogenital neoplasia. ' 2007 Wiley-Liss, Inc.Key words: human papillomavirus; leptomycin B; keratinocytes; oncogenes; apoptosis Leptomycin B (LMB), a secondary metabolite produced by Streptomyces spp., 1 inhibits the export of proteins containing a nuclear export signal (NES) from the nucleus to the cytoplasm. This is achieved through inactivation of the nuclear export receptor protein CRM1 (exportin 1) by covalent modification. 2,3 LMB therefore promotes nuclear accumulation of NES proteins, including the tumour suppressor protein p53. 4,5 Furthermore, LMB has been shown to cause nuclear sequestration and reactivation of p53 in cervical carcinoma cell lines containing human papillomavirus (HPV) and this was associated with induction of apoptosis. 6,7 By contrast, LMB treatment resulted in the reversible cell-cycle arrest of both rat fibroblasts 8 and normal human primary fibroblasts. 5,9 Although the effect of LMB on CRM1 is well documented, the specific molecular mechanism(s) by which LMB induces cellcycle arrest and apoptosis still remain unclear.Since the discovery of LMB in the early 1980s, there has been considerable interest in the use of the compound as a cancer therapeutic. LMB (alternatively termed CI-940, elactocin or PD 114, 720) and its hydroxy analogue (PD 114, 721) were shown to possess potent activity against 7 different tumour models. 10 Based on these encouraging findings, a phase I clinical trial was initiated to assess the systemic administration of LMB. However, the trial was later terminated because of unwanted side effects. 11 Nevertheless, although there are difficulties in using LMB systemically, topical therapeutic use may be feasible.Cervical cancer is the ...

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Systematic Review of Genomic Integration Sites of Human Papillomavirus Genomes in Epithelial Dysplasia and Invasive Cancer of the Female Lower Genital Tract

Cited by 402 publications

References 43 publications

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes

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