Distinct patterns of alteration of myc genes associated with integration of human papillomavirus type 16 or type 45 DNA in two genital tumours

Sastre-Garau, Xavier; Favre, Michel; Couturier, Jérôme; Orth, Gérard

doi:10.1099/0022-1317-81-8-1983

Cited by 37 publications

(32 citation statements)

References 46 publications

(97 reference statements)

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“…Multiple integrations into specific chromosomal loci may be indicative of genes that are common mutational targets in cervical carcinomas. In addition, HPV integration within or near genes that are known to be involved in carcinogenesis has been observed in cervical tumors and cell lines (Choo et al, 1995;Wilke et al, 1996;Sastre-Garau et al, 2000). Indeed, one HPV integration has been shown to occur directly within a gene that has tumor-suppressive properties in cervical cell lines (Reuter et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Thorland¹,

Myers²,

et al. 2003

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“…Fluorescence in situ hybridization experiments Human papillomavirus DNA sequences have been found previously localized by FISH at chromosome bands 8q24.1 in IC1, IC2, IC3 and 2p24 in IC4 (Couturier et al, 1991) and colocalized with MYC and MYCN in IC2 and IC4, respectively (Sastre-Garau et al, 2000). In the present study, FISH experiments were performed for IC5, IC6, IC7, IC8 and CAC-1 cells, according to the procedure previously described (Sastre-Garau et al, 2000).…”

Section: Methodsmentioning

confidence: 98%

“…In the present study, FISH experiments were performed for IC5, IC6, IC7, IC8 and CAC-1 cells, according to the procedure previously described (Sastre-Garau et al, 2000). After chromosomal localization of HPV DNA sequences, metaphase preparations of IC1, IC3, IC6 and CAC-1 were further analysed by dual-color FISH, using HPV16 or 18 probe and a SpectrumOrange labeled MYC probe (Vysis, Downers Grove, IL, USA) in the hybridization mixture.…”

Section: Methodsmentioning

confidence: 99%

“…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. This prompted us to further study HPV integration sites at the molecular level and MYC status/expression by quantitative polymerase chain reaction (PCR) and Western blot in the IC1, IC2 and IC3 cell lines previously analysed, as well as in IC4 cells (Couturier et al, 1991;Sastre-Garau et al, 2000) and in five other cell lines newly established from cervical carcinoma. In five of the nine cell lines, HPV DNA was found at the MYC locus.…”

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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“…Cell lines (IC1, IC3-8) were established from human primary invasive cervical carcinoma (Couturier et al, 1991;Sastre-Garau et al, 2000). Samples from the primary tumours corresponding to IC5, IC6 and IC8 were included in this series (#25, #16 and #31, respectively).…”

Section: Cervical Tissue Samples and Cell Linesmentioning

confidence: 99%

Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma

et al. 2005

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Specific HPV DNA sequences are associated with more than 90% of invasive carcinomas of the uterine cervix. Viral E6 and E7 oncogenes are key mediators in cell transformation by disrupting TP53 and RB pathways. To investigate molecular mechanisms involved in the progression of invasive cervical carcinoma, we performed a gene expression study on cases selected according to viral and clinical parameters. Using Coupled Two-Way Clustering and Sorting Points Into Neighbourhoods methods, we identified a 'cervical cancer proliferation cluster' composed of 163 highly correlated transcripts. Most of these transcripts corresponded to E2F pathway genes controlling cell division or proliferation, whereas none was known as TP53 primary target. The average expression level of the genes of this cluster was higher in tumours with an early relapse than in tumours with a favourable course (P ¼ 0.026). Moreover, we found that E6/E7 mRNA expression level was positively correlated with the expression level of the cluster genes and with viral DNA load. These findings suggest that HPV E6/E7 expression level plays a key role in the progression of invasive carcinoma of the uterine cervix via the deregulation of cellular genes controlling tumour cell proliferation. HPV expression level may thus provide a biological marker useful for prognosis assessment and specific therapy of the disease.

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Distinct patterns of alteration of myc genes associated with integration of human papillomavirus type 16 or type 45 DNA in two genital tumours

Cited by 37 publications

References 46 publications

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

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

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

Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma

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