Integration of human papillomavirus type-16 and type-18 is a very early event in cervical carcinogenesis

Huang, Lee-Wen; Chao, Shiouh-Lirng; Lee, Bor-Heng

doi:10.1136/jcp.2007.052027

Cited by 36 publications

(40 citation statements)

References 28 publications

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Section: Discussionsupporting

confidence: 82%

“…This finding is consistent with recent cross-sectional studies describing the detection of integrated forms of HPV16 and HPV18 in women with low-grade CIN (32)(33)(34). The true incidence of integration events is almost certainly higher than we report because our assay was not designed to identify what are often described as ''mixed infections, '' i.e., those in which E2 continues to be detected because both episomal and integrated forms are present (32)(33)(34), nor could this assay reveal multicopy head-to-tail tandem repeat integrations in which E2 continues to be detected because only the flanking copies are disrupted (26). Unlike HPV18-associated cancers and high-grade CIN, in almost all of which an intact E2 gene can no longer be detected, head-to-tail tandem repeats have been reported in HPV16-associated tumors: this pattern of integration might offer a partial explanation for why we found that HPV18 E2 disruption was more common in our cohort (1,8,25,(35)(36)(37)(38).…”

Section: Discussionsupporting

confidence: 82%

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Disruption of the E2 Gene Is a Common and Early Event in the Natural History of Cervical Human Papillomavirus Infection: A Longitudinal Cohort Study

Collins

Constandinou-Williams

Kong

et al. 2009

Cancer Research

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Integration of high-risk human papillomavirus (HPV) types into the host-cell genome disrupts the HPV regulatory E2 protein, resulting in a loss of negative feedback control of viral oncogene expression; this disruption has been considered a critical event in the pathogenesis of cervical neoplasia, and a potential biomarker of progressive disease. However, using serial samples taken from a cohort of young women who were recruited soon after they first had sexual intercourse, we show that disruption of the E2 gene is a common and early event in the natural history of incident cervical HPV infections. The E2 gene was significantly more likely to be disrupted in women who tested positive for HPV18 in their baseline sample than in those who tested positive for HPV16 [26% versus 58%; relative risk, 2.26; 95% confidence interval (CI), 1.38-3.71; C 2 , 9.23; 1 degree of freedom (df); P = 0.002]. Among women with an intact E2 gene in their baseline sample, the median time to first detection of E2 disruption was also shorter for those who tested positive for HPV18 than HPV16 (5.7 versus 10.9 months; hazards ratio, 1.93; 95% CI, 0.84-4.44; C 2 , 2.49; 1 df; P = 0.11).This tendency for HPV18 to integrate early, coupled with the substantial reduction in viral load in HPV18-positive samples in which E2 is disrupted, may explain why HPV18-associated disease is often reported to be characterized by minor cytologic changes, which underestimate the severity of the underlying histologic abnormality. [Cancer Res 2009; 69(9):3828-32]

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Disruption of the E2 Gene Is a Common and Early Event in the Natural History of Cervical Human Papillomavirus Infection: A Longitudinal Cohort Study

Collins

Constandinou-Williams

Kong

et al. 2009

Cancer Research

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“…The opinions and data concerning the relationship between the HPV integration and the level of cervical intraepithelial lesions differ according to various authors. Some researchers suggest that integration of HPV is an early event of carcinogenesis [25,26], while others believe that integration is more frequently detected in already existing significant intraepithelial changes [8,9]. However, there is no doubt about the importance of HPV integration and its influence on cervical changes.…”

Section: Discussionmentioning

confidence: 99%

State of HPV16 integration in Lithuanian women with cervical neoplasia

et al. 2011

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AbstractCervical cancer morbidity and mortality in Lithuania is one of the biggest in the European Union. The main risk factor of cervical cancer is human papillomavirus (HPV). The deletion of the HPV E2 gene influences HPV DNA integration into the cell genome, as well as a rapid progression of cervical lesions. The purpose of this study is to determine HPV, its types, and HPV 16 integration in different grades of cervical intraepithelial neoplasias (CIN). 253 women with cytological lesions were involved in the study. After a histology, 31 women were diagnosed with CIN I, 35 with CIN II, and 51 with CIN III. The biggest prevalence of HPV infection was detected in women younger than 25 years old (69.7%) and in women with CIN II (90.9%). HPV 16 was detected in 67.8% of all cases, with the highest prevalence in CIN III (84.4%). A partial integration form was detected in 65.0% of HPV 16 infected women, a complete virus integration in 26.5%, and an episomal form in 8.4% of cases. Our study concludes that in all the cases confirmed using a histology, the partial virus integration form of CIN was identified the most. It was less frequently detected in CIN I cases (60.0%), but more frequently in CIN II and CIN III cases (72.8 and 69.3%, respectively).

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mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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Integration of human papillomavirus type-16 and type-18 is a very early event in cervical carcinogenesis

Cited by 36 publications

References 28 publications

Disruption of the E2 Gene Is a Common and Early Event in the Natural History of Cervical Human Papillomavirus Infection: A Longitudinal Cohort Study

Disruption of the E2 Gene Is a Common and Early Event in the Natural History of Cervical Human Papillomavirus Infection: A Longitudinal Cohort Study

State of HPV16 integration in Lithuanian women with cervical neoplasia

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

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