Preferential integration of human papillomavirus type 18 near the c-myc locus in cervical carcinoma

Ferber, Matthew J.; Thorland, Erik C.; Brink, Antoinette A. T. P.; Rapp, Anton K; Phillips, Leslie A.; McGovern, Renee M.; Gostout, Bobbie S.; Cheung, Tak Hong; Chung, Tony K.H.; Fu, Wong Yick; Smith, Jeremy C.

doi:10.1038/sj.onc.1207006

Cited by 159 publications

(135 citation statements)

References 49 publications

(71 reference statements)

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“…HPV18 is frequently associated with adenocarcinoma (Lombard et al, 1998) and preferentially integrates at the MYC locus (Ferber et al, 2003b). However, we and others (Brink et al, 2002;Wentzensen et al, 2002) have also found HPV16 DNA at this locus.…”

Section: Discussionmentioning

confidence: 47%

“…It is important to underline that, comparing the histological type of cervical carcinomas, when it was documented, to the cartography of viral integration sites (present study and (Thorland et al, 2000;Klimov et al, 2002;Ferber et al, 2003b), 9/10 cases with HPV DNA sequences at the MYC locus corresponded to adenocarcinomas, whereas 22/29 of cases with viral sequences at other sites were squamous cell carcinoma (P ¼ 4.10 À4 ). HPV18 is frequently associated with adenocarcinoma (Lombard et al, 1998) and preferentially integrates at the MYC locus (Ferber et al, 2003b).…”

Section: Discussionmentioning

confidence: 50%

“…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to 243 cases have been observed (Brink et al, 2002;Klimov et al, 2002;Wentzensen et al, 2004;Kraus et al, 2005;and our unpublished results).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). A low level of MYC overexpression has been found in HeLa cells harboring HPV18 sequences in chromosome band 8q24 (Du¨rst et al, 1987;Lazo et al, 1989), but no evidence of MYC activation directly related to HPV insertion at the MYC locus has been published.…”

Section: Discussionmentioning

confidence: 99%

“…Besides MYC, a number of genes, potentially involved in carcinogenesis, such as CEACAM5, FANCC (Wentzensen et al, 2002;Ferber et al, 2003b), TP63 (Wentzensen et al, 2002), TERT (Ferber et al, 2003a), MYOF, Ribosomal protein gene RPS27 (Klimov et al, 2002), MYCN (Sastre-Garau et al, 2000), NFIB (Ziegert et al, 2003), have also been found to correspond to targets for the insertion of HPV DNA. In spite of this diversity, only a few cases with an integration pattern compatible with a mechanism of insertional mutagenesis have been observed (Wentzensen et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…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: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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Cis‐regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers

Singh,

Walavalkar,

Tavernari

et al. 2023

Molecular Oncology

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Human papillomavirus (HPV) infections are the primary drivers of cervical cancers, and often HPV DNA gets integrated into the host genome. Although the oncogenic impact of HPV encoded genes is relatively well known, the cis‐regulatory effect of integrated HPV DNA on host chromatin structure and gene regulation remains less understood. We investigated genome‐wide patterns of HPV integrations and associated host gene expression changes in the context of host chromatin states and topologically associating domains (TADs). HPV integrations were significantly enriched in active chromatin regions and depleted in inactive ones. Interestingly, regardless of chromatin state, genomic regions flanking HPV integrations showed transcriptional upregulation. Nevertheless, upregulation (both local and long‐range) was mostly confined to TADs with integration, but not affecting adjacent TADs. Few TADs showed recurrent integrations associated with overexpression of oncogenes within them (e.g. MYC, PVT1, TP63 and ERBB2) regardless of proximity. Hi‐C and 4C‐seq analyses in cervical cancer cell line (HeLa) demonstrated chromatin looping interactions between integrated HPV and MYC/PVT1 regions (~ 500 kb apart), leading to allele‐specific overexpression. Based on these, we propose HPV integrations can trigger multimodal oncogenic activation to promote cancer progression.

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Human papillomavirus infection and biomarkers in sinonasal inverted papillomas: clinical significance and molecular mechanisms

Scheel

Lin

McHugh

et al. 2015

Int Forum Allergy Rhinol

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Background The role of HPV in sinonasal inverted papillomas (IP) is controversial. Determining the prevalence of HPV infection and its impact on the molecular biology of these tumors is critical to characterizing its role in the pathogenesis of inverting papillomas. Methods A total of 112 paraffin embedded IPs from 90 patients were studied. A tissue microarray was constructed and stained for p16, p53, EGFR and cyclin D1. HPV presence and type were determined using PGMY 09/11 primers and integration using HPV 11 DIPS-PCR. Results HPV was detected in 11/90(12%) of patients. HPV 11 was found in 9 samples. HPV 6 and HPV 27 were found in one sample each. EGFR staining proportion was higher in HPV positive IPs vs. HPV negative specimens (56.2 vs. 23.6%; p=0.009). Differences in p16, p53 and cyclin D1 staining were not significant. HPV positive lesions tend to progress to malignancy (p=0.064). Three samples were analyzed for integration. Viral integration was found in both malignant tumors but not in the precursor IP. Conclusions Degradation of p53 and p16/cyclin D1disregulation are not important mechanisms in low risk HPV related IP. The low prevalence of HPV in this series indicates it is not a main etiological factor for IPs, however, when present, low risk HPV may contribute to the biology of IPs through an increase of EGFR expression and a predisposition for malignant progression by integration into the cellular genome.

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Preferential integration of human papillomavirus type 18 near the c-myc locus in cervical carcinoma

Cited by 159 publications

References 49 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

Cis‐regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers

Human papillomavirus infection and biomarkers in sinonasal inverted papillomas: clinical significance and molecular mechanisms

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