Human papillomavirus DNA integration and messenger RNA transcription in cervical low- and high-risk squamous intraepithelial lesions in Austrian women

Manavi, M.; Hudelist, Gernot; Fink-Retter, A.; Gschwantler‐Kaulich, Daphne; Pischinger, K.; Czerwenka, K.

doi:10.1111/j.1525-1438.2007.01017.x

Cited by 12 publications

(13 citation statements)

References 47 publications

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“…For reasons of safety, these lesions are usually surgically resected. Our findings support previous suggestions that some women who undergo surgical resection may be overtreated (12,26,27,29,32).…”

Section: Discussionsupporting

confidence: 82%

“…This suggests that the virus was present only at very low copy numbers and/or that only a specific region of viral DNA was integrated into the host genome. The loss of the L1 gene and its impact on viral replication after integration could lead to relatively low viral loads (7,15,24,32). Given that malignant phenotypes require continuous expression of the E6 and E7 oncogenes (13,27,39,57) and that they produce transcripts throughout the epithelium and the surface layers (12,15), it is not surprising that RNA assays detect more clinically significant infections than DNA testing, especially when samples come from the surface layers of the cervical epithelium, as in the present study.…”

Section: Discussionmentioning

confidence: 67%

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Clinical Performance of Human Papillomavirus E6 and E7 mRNA Testing for High-Grade Lesions of the Cervix

et al. 2009

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Infection with high-risk (HR) human papillomavirus (HPV) is the major cause of cervical cancer. However, relatively few infections progress to malignant disease. Progression to malignancy requires the overexpression of the E6 and E7 genes in the integrated HPV genome. It follows that the E6 and E7 transcripts could be useful markers of disease progression. The study presented here tests this possibility, using data from colposcopy and from cytological and histological tests to compare RNA assays for the E6 and E7 genes with DNA testing. A total of 180 women underwent colposcopy, cytology, and biopsy of suspected lesions (143 cases). Cervical brush specimens were analyzed for HPV DNA and for E6 and E7 mRNA. DNA from HR HPV was found in 57.8% of the specimens; E6 and E7 transcripts were found in 45%. The rates of detection of HPV DNA and of E6 and E7 transcripts were 33.3% and 25%, respectively, for specimens with normal findings; 51.4% and 31.9%, respectively, for specimens with cervical intraepithelial neoplasia grade 1 (CIN1); and 61.1% and 44.2% for specimens with CIN2, respectively. All specimens with CIN3 and 95.5% of specimens from patients with squamous cell carcinoma were positive by both assays. Thirty-seven patients with normal colposcopy findings did not undergo biopsy. HPV DNA and mRNA transcripts were found in 32.4% and 18.9% of these cases, respectively. Comparisons with cytological tests produced similar results. Overall, the mRNA tests showed a higher specificity than the DNA tests for high-grade lesions (72.7% and 56.2%, respectively) and a higher positive predictive value (59.3% and 49.0%, respectively). These findings suggest that mRNA assays could be more powerful than DNA testing for predicting the risk of progression and offer a strong potential as a tool for triage and patient follow-up.Carcinomas of the anogenital tract, particularly cancer of the cervix, represent the second most frequent type of neoplasm worldwide (43, 57). The major cause of these cancers is infection with high-risk (HR) human papillomavirus (HPV). DNA from HPV has been detected in more than 99% of cervical squamous cell carcinomas (SCCs) and a smaller proportion of adenocarcinomas (3,4,31,33). However, most HPV infections regress spontaneously or progress only after a long period of latency. As a result, the number of infections is far higher than the number of women who develop cancer.The most common types of HPV found in cancer patients are types 16, 18, 31, 33, and 45 (5, 10, 40, 53). Persistent infection with these types is regarded as a significant risk factor (40). The role of HPVs in the etiology of cervical cancer is tightly correlated with the overexpression of two oncogenes (E6 and E7) due to a specific opening in the E2 open reading frame in the integrated viral genome (23, 28). Studies of cervical cancer cell lines and cancer biopsy specimens have shown that the continuous expression of the genes is a necessary condition for the transformation and maintenance of neoplastic and dysplastic cells (46,56,57).Ce...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 67%

Clinical Performance of Human Papillomavirus E6 and E7 mRNA Testing for High-Grade Lesions of the Cervix

et al. 2009

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“…Many previous studies have found that almost all HPV18 infections exist in an integrated form in women with invasive cancer (2,9,15,22,32). In the current study, we found a rather high proportion of ICC (57.1%) harboring only the episomal form of the virus.…”

Section: Discussionsupporting

confidence: 61%

“…We believe one explanation for this discrepancy could be the sensitivity of the method used. Methods such as Southern blotting or two-dimensional gel electrophoresis were often employed to document the physical state of the HPV genome in previous studies (2,9,10,22,27). One disadvantage of these methods is that they often require a large amount of DNA to produce a positive signal.…”

Section: Discussionmentioning

confidence: 99%

“…HPV18 has been found to be strongly associated with adenocarcinoma of the cervix. Studies carried out with HPV18 have shown that the viral genome is almost invariably found to be integrated in highgrade cervical intraepithelial lesions and invasive cancers (2,9,22,27,32), and these findings potentially allow the use of integration status as a marker to triage HPV18 infections with different clinical implications. However, such applications should be supported by data generated from a large series of clinical samples.…”

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confidence: 99%

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Analysis of Human Papillomavirus Type 18 Load and Integration Status from Low-Grade Cervical Lesion to Invasive Cervical Cancer

Cheung¹,

Cheung²,

Ng³

et al. 2009

J Clin Microbiol

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The clinical value of viral load and integration testing for human papillomavirus (HPV) remains unclear. Data on HPV type 18 (HPV18) is limited. We examined the HPV18 viral load and integration status of 78 women with normal cervix or neoplasia. While the crude viral load appeared to increase with lesion severity, the association was not significant after normalization with sample cellularity. Unlike reports for HPV16, the amino-terminal 1 region of HPV18 E2 was most frequently (71.0%) disrupted, representing the best marker for integration. A substantial proportion (57.1%) of invasive cancers harbored only the episomal genome, thus jeopardizing the clinical value of integration testing. A large proportion (41.7%) of normal/low-grade lesions showed viral integration, suggesting that integration of HPV18 starts early and is unlikely to be a sole determinant for progression. Interpretation of viral load should take into account the form of HPV infection as single infections had significantly higher viral loads than coinfections (P ‫؍‬ 0.046). More data generated from routinely collected samples are warranted to verify the clinical value of viral load and integration testing. Viral load quantitation for HPV18 is premature for clinical use at this stage.There is no doubt that infection with human papillomavirus (HPV) may lead to the establishment of cervical cancer (3, 33). Though infection with HPV is common, not all HPV types will lead to cancer. There are 15 high-risk HPV types that have a higher propensity for the development of cervical cancer, with HPV type 16 (HPV16) and HPV18 being the most prevalent high-risk types worldwide (8,25).Women who have tested positive for high-risk HPV tend to harbor abnormal cervical cytology, and some studies have reported a correlation between viral load and disease severity (19,20,24,28,31). However, the consistency of these findings has been questioned, and it is now realized that the relationship is a lot more complex (5-7, 35). As the severity of disease increases, HPV is often found integrated into the host genome, making the interpretation of viral load even more complex. Furthermore, the available viral load data have been generated using different methodologies that may not be directly comparable (13,17,28,29).The HPV genome can exist in two physical forms: a closed circular episomal form or linearized and integrated into the host genome. Integration of the viral genome is often associated with the disruption of the E2 gene, which has regulatory control of the oncogenes E6 and E7. Nevertheless, this concept has been questioned by a recent study where the integration of the HPV16 genome was not necessarily associated with the overexpression of E6 and E7 (14). HPV18 has been found to be strongly associated with adenocarcinoma of the cervix. Studies carried out with HPV18 have shown that the viral genome is almost invariably found to be integrated in highgrade cervical intraepithelial lesions and invasive cancers (2,9,22,27,32), and these findings potentially allow the us...

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Viral load and physical status of human papillomavirus (HPV) 18 in cervical samples from female sex workers infected with HPV 18 in Burkina Faso

Damay

Didelot-Rousseau

Costes

et al. 2009

Journal of Medical Virology

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Viral DNA load and physical status might be predictive of either high-grade cervical lesions or disease progression among women infected by human papillomavirus (HPV) 16, but these virological markers have rarely been studied in HPV 18 infections. The relationships between HPV 18 DNA load, viral genome physical status and cervical squamous intraepithelial lesions were analyzed among female sex workers infected with HPV18 in Burkina Faso. HPV 18 E2 and E6 genes were quantitated by real-time PCR. Among 21 women infected with HPV 18, 67% of whom were HIV-1-seropositive, 11 (52.4%) had a normal cytology, 8 (38.1%) had low-grade squamous intraepithelial lesions, and 2 (9.5%) had high-grade squamous intraepithelial lesions. Total viral load and integrated viral load were higher in women with squamous intraepithelial lesions than in women with normal cytology (P = 0.01 for both parameters). Total viral load and integrated viral load were higher in HIV-1-seropositive women than in those who were not infected with HIV (P = 0.01, and P, 0.01, respectively). Total viral load or integrated viral load >1,000 copies/ng of DNA were more frequent in women with squamous intraepithelial lesions than in women with normal cytology (7/10 vs. 1/11; P = 0.007) and in HIV-1-seropositive women (8/14 vs. 0/7 in HIV-uninfected women; P = 0.02). Both HPV 18 DNA and integrated DNA loads might represent markers of cervical lesions. Prospective evaluations are needed to establish the value of these parameters to predict high-grade lesion or lesion progression.

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Human papillomavirus DNA integration and messenger RNA transcription in cervical low- and high-risk squamous intraepithelial lesions in Austrian women

Cited by 12 publications

References 47 publications

Clinical Performance of Human Papillomavirus E6 and E7 mRNA Testing for High-Grade Lesions of the Cervix

Clinical Performance of Human Papillomavirus E6 and E7 mRNA Testing for High-Grade Lesions of the Cervix

Analysis of Human Papillomavirus Type 18 Load and Integration Status from Low-Grade Cervical Lesion to Invasive Cervical Cancer

Viral load and physical status of human papillomavirus (HPV) 18 in cervical samples from female sex workers infected with HPV 18 in Burkina Faso

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