Human Papillomavirus Type 16 Integration in Cervical Carcinoma In Situ and in Invasive Cervical Cancer

Arias-Pulido, Hugo; Peyton, Cheri L.; Joste, Nancy E.; Vargas, Hernan I.; Wheeler, Cosette M.

doi:10.1128/jcm.44.5.1755-1762.2006

Cited by 207 publications

(230 citation statements)

References 40 publications

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“…Using 12 cervical cancer samples positive for HPV 16 (unpublished data), we determined E2/E6 ratio and found that 92% of the samples had a mixture of episomal and integrated forms of HPV genome, and 8% of the samples had HPV integrated into the host genome. The method, similar to ours, showed that 65 -97% of the cervical cancer cases had HPV 16 integration, which was frequently accompanied by episomal-form HPV (Peitsaro et al, 2002;Arias-Pulido et al, 2006). In the present study, a viral load in each specimen was expressed as the number of HPV copies/genome equivalent or cell, using a conversion factor of 6.6 pg of DNA cell À1 in order to make comparisons with the results of other studies (Si et al, 2003).…”

Section: Discussionmentioning

confidence: 69%

Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China

et al. 2007

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To examine the potential roles of human papillomavirus (HPV) in oesophageal squamous cell carcinoma (ESCC) development, we examined the presence of HPV DNA in paraffin-embedded ESCC tissues collected from two areas with different ESCC incidence rates in China, that is, Gansu (n ¼ 26) and Shandong (n ¼ 33), using PCR with SPF10 primers, or PCR with GP5 þ /GP6 þ primers combined with Southern blot hybridisation. HPV genotype was determined by the INNO-LiPA HPV genotyping kit. HPV DNA was detected in 17 cases (65%) in Gansu, where ESCC incidence is much higher than in Shandong, where HPV was positive in two samples (6%). HPV genotypes 16 and 18 were detected in 79 and 16% of HPV-positive samples, respectively. Real-time PCR analysis suggested the presence of integrated form of HPV DNA in all the HPV-16-positive samples, but its viral load was estimated to be only o1 -2 copies cell À1 . We could not detect HPV 16/18 E6 protein expression by immunostaining in any of the HPV-16-positive samples. Neither p16 INK4a nor p53 expression was related to HPV presence in ESCCs. Further studies seem warranted to examine the possible aetiological roles of HPV in ESCC.

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Section: Discussionmentioning

confidence: 69%

Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China

et al. 2007

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“…the nearly complete lack of methylation at position 7862 in all samples, and the selective hypermethylation of promoter sequences in some samples, have become a recurrent theme of HPV-16 methylation patterns in any anatomic site, and are clearly properties of the viral DNA irrespective of the anatomical site of the affected host cell. It has been pointed out by others 35 that promoter methylation may favor carcinogenesis, as it prohibits binding of the E2 protein, 38 which is a repressor of the E6 promoter, and assures continued oncogene expression even in the subpopulation of lesions that did not lose E2 as a consequence of genomic interruption. 39 The data of this study and our previous studies provide strong support that the measurement of DNA methylation is a useful biomarker to characterize malignant lesions.…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus‐16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas

Balderas-Loaeza

Anaya‐Saavedra

Ramírez‐Amador

et al. 2007

Intl Journal of Cancer

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Infection with human papillomavirus-16 (HPV-16) is the cause of most anogenital carcinomas. This virus is also detected in about 20% of all head and neck squamous cell carcinomas. While there is strong evidence for a causal etiological role in the case of tonsillar carcinomas, causal association with malignant lesions of the oral cavity is not yet conclusive. Our previous investigations of HPV-16 DNA methylation in anogenital sites have identified hypermethylation of the L1 gene and part of the long control region in many malignant lesions, but rarely in asymptomatic infections and low-grade precancerous lesions. Here, we report hypermethylation of this diagnostically important segment of the viral DNA in 10 out of 12 HPV-16 positive oral carcinomas from Mexican patients. These data indicate epigenetic changes of HPV-16 in oral carcinomas similar to those in anogenital carcinomas, suggesting carcinogenic processes under the influence of HPV-16 in most if not all of these oral malignant lesions. ' 2007 Wiley-Liss, Inc.Key words: papillomavirus; carcinoma; head and neck cancer; oral cavity; DNA methylation; DNA recombination; etiology; progression; Infection with human papillomaviruses (HPVs), notably with high-risk HPV types such as HPV-16 and 18, is a necessary step in the etiology of anogenital cancers, specifically carcinoma of the cervix uteri. This notion is based on epidemiological research that identified a high relative risk of carcinogenic progression associated with high-risk HPV infection, DNA diagnosis that confirmed the presence and transcription of HPV genomes in all cervical carcinomas, and the study of HPV oncoproteins that catalyze a variety of molecular mechanisms that convert normal into malignant cells. [1][2][3][4][5][6] In case of head and neck squamous cell carcinomas (HNSCCs), an HPV dependent etiology is not as consistently confirmed as in anogenital cancers. Approximately 80% of all HNSCCs do not contain HPV genomes, and must therefore originate from HPV independent etiological processes, likely including mutational events triggered by tobacco and alcohol consumption. However, there is extensive evidence that a proportion of all HNSCCs contain DNA of high-risk HPV types. 7-14 Among head and neck sites, squamous cell carcinomas of the tonsils have the strongest statistical support for an HPV dependent etiology. 9,[15][16][17] There is less strength and consistency for a linkage between HPV infection and carcinogenesis at sites of the oral mucosa such as tongue, palate, floor of mouth and gingiva. Nevertheless, epidemiological studies have established statistical evidence for a causal association of HPVs and malignancies even for these oral sites. 9,16 In addition, analysis of some HPV containing oral carcinomas revealed recombination between HPV genomes and cellular DNA as well as HPV oncogene expression, [10][11][12][13][18][19][20] properties that are generally viewed as support of carcinogenic processes under the influence of HPVs. On the basis of these observations one must conclude ...

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“…17,18 In most published studies of cervical carcinoma, the integrated forms of HPV 16 were also observed in either all or a majority of the specimens. 42,43 AriasPulido et al 22 recently conducted a study of formalin-fixed paraffin-embedded as well as fresh cervical specimens using qRT-PCR and reported a relatively low proportion of the integrated type of HPV 16 in carcinoma in situ (30.3%) and in invasive carcinoma (60.9%). The discrepancies of HPV 16 integration in the published studies may be resulted by different primers targeting different E1 or E2 regions and the effect of the adjacent tissue around the targeted lesion.…”

Section: Discussionmentioning

confidence: 99%

“…This occurs by disruption or deletion of the viral E1 and/or E2 open reading frame, which releases the suppressive effect of the E2 protein on the viral oncogenes E6 and E7, leading to the activation of E6 and E7 transcription. [19][20][21][22] The E6 and E7 oncogenic potencies of HPV 16 is clearly associated with promoting the transformation and immortalization of infected cells. 23 Consequently, HPV 16 integration provides a selective growth advantage in the infected cells and is associated with treatment failure or a shortened disease-free survival.…”

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confidence: 99%

Distribution and viral load of eight oncogenic types of human papillomavirus (HPV) and HPV 16 integration status in cervical intraepithelial neoplasia and carcinoma

et al. 2007

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Current human papillomavirus (HPV) DNA testing using pooled probes, although sensitive, lacks specificity in predicting the risk of high-grade cervical intraepithelial neoplasia (CIN 2/3) progression. To evaluate selected HPV genotyping, viral load, and viral integration status as potential predictive markers for CIN progression, we performed HPV genotyping in formalin-fixed, paraffin-embedded cervical tissue with cervical carcinoma (29 cases) and CINs (CIN 1, 27 cases; CIN 2, 28 cases; CIN 3, 33 cases). General HPVs were screened using consensus primers GP5 þ /GP6 þ and PGMY09/11. HPV genotyping and viral load measurement were performed using quantitative real-time PCR for eight oncogenic HPV types (16, 18, 31, 33, 35, 45, 52, and 58). HPV 16 viral integration status was evaluated by measuring HPV 16 E2/E6 ratio. We observed that HPV DNA positivity increased in parallel with the severity of CINs and carcinoma, with 59% positivity in CIN 1, 68% in CIN 2, 76% in CIN 3, and 97% in carcinoma (P trend ¼ 0.004). The eight oncogenic HPV types were significantly associated with CIN 2/3 (81%) and carcinoma (93%) (odds ratio (OR), 15.0; 95% confidence interval (CI), 5.67-39.76; Po0.0001) compared with the unknown HPV types (OR, 2.87; 95% CI, 0.89-9.22; P ¼ 0.08). HPV 16 was the predominant oncogenic HPV type in CIN 2/3 (51%) and carcinoma (71%) and integrated significantly more frequently in carcinoma than in CIN 2/3 (P ¼ 0.004). No significant differences in viral load were observed across the disease categories. Our findings suggest that selected genotyping for the eight oncogenic HPV types might be useful in separating women with a higher risk of CIN progression from those with a minimal risk. We also conclude that the HPV 16 integration status has potential to be a marker for risk assessment of CIN progression.

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Human Papillomavirus Type 16 Integration in Cervical Carcinoma In Situ and in Invasive Cervical Cancer

Cited by 207 publications

References 40 publications

Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China

Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China

Human papillomavirus‐16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas

Distribution and viral load of eight oncogenic types of human papillomavirus (HPV) and HPV 16 integration status in cervical intraepithelial neoplasia and carcinoma

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