Disruption of HPV 16 E1 and E2 genes in precancerous cervical lesions

Cricca, Monica; Venturoli, Simona; Leo, Elisa; Costa, Silvano; Musiani, Monica; Zerbini, Marialuisa

doi:10.1016/j.jviromet.2009.01.005

Cited by 42 publications

(50 citation statements)

References 23 publications

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“…Successful integration results in greater expression of HPV E6/ E7 and more stable transcripts. When viral episomes are integrated, the E2 gene is disrupted and E2 expression decreases (27,28). When E2 levels decrease, expression of integrated E6/E7 becomes uninhibited and E2-mediated apoptosis also declines (29)(30)(31).…”

Section: Subtotal (95% Ci)mentioning

confidence: 99%

p53 Arg72Pro Polymorphism, HPV Status and Initiation, Progression, and Development of Cervical Cancer: A Systematic Review and Meta-Analysis

Habbous

Pang

Eng

et al. 2012

Clinical Cancer Research

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Cervical cancer develops through progression from normal cervical epithelium through squamous intraepithelial lesions (SIL) to invasive cancer. Cervical cancer is associated with oncogenic human papillomavirus (HPV). The HPV E6 oncoprotein binds to the tumor suppressor gene product p53, promoting its degradation; the Arg allele of p53 Arg72Pro polymorphism binds more ardently with HPV E6 than the Pro variant. Here we evaluate the role of p53 Arg72Pro polymorphism and HPV status on the initiation, progression, and development of cervical cancer. A systematic review and meta-analysis were conducted. Events of interest were the initiation of neoplasia (SIL vs. normal), progression to invasive cancer (cervical cancer vs. SIL), and risk of invasive cancer (cervical cancer vs. normal) by HPV status. OR were extracted from individual studies and pooled using generic inverse variance and random effects modeling. Forty-nine studies were included. In individuals showing HPV positivity, there was a significantly higher odds of progression from SIL to cervical cancer with the p53 Arg allele [OR 1.37; 95% confidence intervals (CI), 1.15-1.62; P < 0.001]. This association was not seen in HPVnegative individuals. p53 Arg72Pro was not associated with the risk of cervical cancer or initiation of SIL in either HPV-positive or HPV-negative patient subsets. The Arg variant of p53 Arg72Pro is associated with progression of SIL to cervical cancer only in the presence of HPV positivity. There were no associations of this variant with overall risk or initiation of cancer in either HPV-positive or HPVnegative patients.

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Section: Subtotal (95% Ci)mentioning

confidence: 99%

p53 Arg72Pro Polymorphism, HPV Status and Initiation, Progression, and Development of Cervical Cancer: A Systematic Review and Meta-Analysis

Habbous

Pang

Eng

et al. 2012

Clinical Cancer Research

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“…The infection rate with high-risk HPV has been reported to be as low as 7.25% in women of Uygur ethnicity in Xinjiang Hotan Prefecture (7)(8)(9), compared with 12.1% in women of Han ethnicity (10). By contrast, the cervical cancer morbidity rate in women of Uygur ethnicity has been reported to be as high as 526 per 100,000 (11).…”

Section: Introductionmentioning

confidence: 99%

Comparative study of HPV16 integration in cervical lesions between ethnicities with high and low rates of infection with high-risk HPV and the correlation between integration rate and cervical neoplasia

Han

Maimaitiming

Husaiyin

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The etiology of a high incidence of cervical cancer in populations with a low human papillomavirus (HPV) infection rate is unclear. The current study aimed to investigate the role of HPV16 DNA integration in cervical lesions in women of Han and Uygur ethnicity and to explore the association between viral integration and a high cervical cancer morbidity with a low HPV infection rate. DNA was extracted from the biopsy specimens of cervical lesions of 379 patients of Uygur ethnicity and 464 patients of Han ethnicity, and multiple quantitative polymerase chain reaction (qPCR) assays were performed to determine the copy numbers of the HPV16 E2 and E6 genes. The copy number of the HPV16 DNA was evaluated according to the E2/E6 ratio. Among these cases, 122 Uygur and 121 Han specimens were found to be HPV16 positive. In the two populations, the percentage of cases with HPV16 integration (the sum of integrated-type infection only or a mixture of free-and integrated-type infection) increased with the grade of the cervical lesions (P<0.001). Within groups with the same cervical lesion grade, no significant differences in HPV16 integration were found between women of Uygur and Han ethnicity (rank sum test, P>0.05). No significant differences in the distribution of the HPV16 integration rate according to lesion grade were found in either population (P>0.05). When the two subpopulations were considered as one sample population, the integration rate significantly increased with lesion grade (P=0.02). These results indicate that the integration rate of HPV16 E2 may serve as a molecular biological marker for the development of cervical lesions. IntroductionCervical cancer is the second most common malignant tumor in women throughout the world, ranking just behind breast cancer (1). The essential pathogenic factor in cervical cancer is the persistence of high-risk human papillomavirus (HPV), which is a double-stranded DNA virus with a capsid (2).To date, numerous studies have reported on the integration of HPV DNA into the host genome in precancerous uterine cervical lesions and cervical cancers (3). High-risk HPV DNA integration into the host genome is a key factor eliciting malignant transformation in cervical lesions; both the HPV16 integration rate and the persistence of HPV16 infection demonstrate a positive correlation with the cervical lesion grade (4). Although the integration rates of HPV16 and HPV18 DNA increase with an increase in the malignancy level, the mixed type, that is, cases in which both free-type and integrated-type infection is present, is much more frequently observed in HPV16 integration. The integration of HPV16 and HPV18 into the host genome is an early step in cervical tumor development, and the incidence rate of HPV DNA integration increases with the aggravation of cervical lesions (5). HPV DNA integration has been detected in 7.4% of lesion tissues in HPV16-positive precancerous lesions of the uterine cervix, but integration occurs only in severe cervical lesions (6). These findings indicat...

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“…This can be explained by the existence of the viral genome in both episomal and integrated states. Although this phenomenon was not evaluated in our study, it has been previously reported for HPV16 (Peitsaro et al 2002, Cricca et al 2009). Moreover, Manawapat et al (2012) reported the occurrence of both forms of the viral genome in 92% of women without cervical lesions and persistent infection, as well as in 90% of women with HSIL.…”

mentioning

confidence: 65%

“…Therefore, viral DNA integrity has been proposed, albeit controversially (Chan et al 2007, Cricca et al 2009, Manawapat et al 2012), as a possible biomarker for the cancer risk, mainly in cases of infection with HPV16 and/or HPV18 (Oliveira et al 2013, Tsakogiannis et al 2015, Xu et al 2015). In addition, HPV58 viruses have been found to be very frequent in Mexican women with cervical pathology living in the Mayan area (González-Losa & Conde-Ferraez 2013).…”

mentioning

confidence: 99%

Analysis of E2 gene integrity in HPV16 and HPV58 viruses isolated from women with cervical pathology

González-Losa

Puerto-Solı́s

Ruiz

et al. 2016

Mem. Inst. Oswaldo Cruz

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Integration of human papillomavirus (HPV) DNA into human cells accompanied by the disruption of the viral genome has been described as a prerequisite for cancer development. This study aimed to investigate E2 gene integrity of HPV16 and HPV58 viruses isolated from infected women with cervical lesions. Forty-two HPV16- and 31 HPV58-positive samples were analysed. E2 integrity was assumed when all fragments covering the E2 gene were amplified with specific polymerase chain reaction primers. Overall, in 59% of the samples, at least one fragment was not amplified in HPV16- (57%) and HPV58-positive samples (61%). Samples from high-grade squamous intraepithelial lesions had the highest frequency of E2 gene disruptions (73%), followed by samples from low-grade squamous intraepithelial lesions (63%) and, finally, samples from invasive cervical cancer (35%). Association between the integrity status of the E2 gene, and lesion grade was assessed by the chi-squared test applied to the combined set of viruses (p = 0.6555) or to populations of the same virus type (HPV58, p = 0.3101; HPV16, p = 0.3024). In conclusion, in this study, no association was found between the presence of E2 gene disruptions and the grade of cervical lesions caused by HPV16 and HPV58.

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Disruption of HPV 16 E1 and E2 genes in precancerous cervical lesions

Cited by 42 publications

References 23 publications

p53 Arg72Pro Polymorphism, HPV Status and Initiation, Progression, and Development of Cervical Cancer: A Systematic Review and Meta-Analysis

p53 Arg72Pro Polymorphism, HPV Status and Initiation, Progression, and Development of Cervical Cancer: A Systematic Review and Meta-Analysis

Comparative study of HPV16 integration in cervical lesions between ethnicities with high and low rates of infection with high-risk HPV and the correlation between integration rate and cervical neoplasia

Analysis of E2 gene integrity in HPV16 and HPV58 viruses isolated from women with cervical pathology

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