Determinants of Viral Oncogene E6-E7 mRNA Overexpression in a Population-Based Large Sample of Women Infected by High-Risk Human Papillomavirus Types

ABSTRACT Cervical cancer screening by human papillomavirus (HPV) DNA testing with cytology triage is more effective than cytology testing. Compared to cytology, the HPV DNA test's higher sensitivity, which allows better protection with longer intervals, makes it necessary to triage the women with a positive result to compensate its lower specificity. We are conducting a large randomized clinical trial (New Technologies for Cervical Cancer 2 [NTCC2]) within organized population-based screening programs in Italy using HPV DNA as the primary screening test to evaluate, by the Aptima HPV assay (Hologic), the use of HPV E6-E7 mRNA in a triage test in comparison to cytology. By the end of June 2016, data were available for 35,877 of 38,535 enrolled women, 2,651 (7.4%) of whom were HPV DNA positive. Among the samples obtained, 2,453 samples were tested also by Aptima, and 1,649 (67.2%) gave a positive result. The proportion of mRNA positivity was slightly higher among samples tested for HPV DNA by the Cobas 4800 HPV assay (Roche) than by the Hybrid Capture 2 (HC2) assay (Qiagen). In our setting, the observed E6-E7 mRNA positivity rate, if used as a triage test, would bring a rate of immediate referral to colposcopy of about 4 to 5%. This value is higher than that observed with cytology triage for both immediate and delayed referrals to colposcopy. By showing only a very high sensitivity and thus allowing a longer interval for HPV DNA-positive/HPV mRNA-negative women, a triage by this test might be more efficient than by cytology.

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Sensitivity, Specificity, and Clinical Value of Human Papillomavirus (HPV) E6/E7 mRNA Assay as a Triage Test for Cervical Cytology and HPV DNA Test

Journal of Clinical Microbiology ◽

10.1128/jcm.02570-10 ◽

2011 ◽

Vol 49 (7) ◽

pp. 2643-2650 ◽

Cited By ~ 63

Author(s):

Maria Benevolo ◽

Amina Vocaturo ◽

Donatella Caraceni ◽

Deborah French ◽

Sandra Rosini ◽

...

Keyword(s):

Human Papillomavirus ◽

Cervical Cytology ◽

Clinical Value ◽

Dna Test ◽

Hpv Dna ◽

Hpv E6 ◽

Sensitivity Specificity ◽

Triage Test ◽

Hpv Dna Test

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Viral and Cellular Biomarkers in the Diagnosis of Cervical Intraepithelial Neoplasia and Cancer

BioMed Research International ◽

10.1155/2013/519619 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 51

Author(s):

Maria Lina Tornesello ◽

Luigi Buonaguro ◽

Paolo Giorgi-Rossi ◽

Franco M. Buonaguro

Keyword(s):

Cervical Cancer ◽

High Risk ◽

Viral Infections ◽

Invasive Cervical Cancer ◽

High Sensitivity ◽

Intraepithelial Neoplasia ◽

Premalignant Lesions ◽

Low Grade ◽

Hpv Dna ◽

Hpv E6

Cervical cancer arises from cells localized in the ectoendocervical squamocolumnar junction of the cervix persistently infected with one of about 13 human papillomavirus (HPV) genotypes. The majority of HPV infections induces low grade squamous epithelial lesions that in more than 90% of cases spontaneously regress and in about 10% eventually progress to high grade lesions and even less frequently evolve to invasive cancer. Tumor progression is characterized by (1) increased expression of E6 and E7 genes of high risk HPVs, known to bind to and inactivate p53 and pRb oncosuppressors, respectively; (2) integration of viral DNA into host genome, with disruption of E2 viral genes and host chromosomal loci; and (3) molecular alterations of key regulators of cell cycle. Molecular markers with high sensitivity and specificity in differentiating viral infections associated with cellular abnormalities with high risk of progression are strongly needed for cervical cancer screening and triage. This review will focus on the analysis of clinical validated or candidate biomarkers, such as HPV DNA, HPV E6/E7 mRNA, HPV proteins, p16(INK4a) and Ki67, TOP2A and MCM2 cellular factors, and DNA methylation profiles, which will likely improve the identification of premalignant lesions that have a high risk to evolve into invasive cervical cancer.

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Burden of Human Papillomavirus (HPV)-Related Cancers Attributable to HPVs 6/11/16/18/31/33/45/52 and 58

JNCI Cancer Spectrum ◽

10.1093/jncics/pky045 ◽

2018 ◽

Vol 2 (4) ◽

Cited By ~ 27

Author(s):

Silvia de Sanjosé ◽

Beatriz Serrano ◽

Sara Tous ◽

Maria Alejo ◽

Belén Lloveras ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Hpv Vaccine ◽

Hpv Vaccination ◽

Hpv Vaccines ◽

Middle Income ◽

Vaccination Programs ◽

Hpv Dna ◽

Hpv E6 ◽

Potential Impact

Abstract Background Many countries, mainly high- and upper-middle income, have implemented human papillomavirus (HPV) vaccination programs, with 47 million women receiving the full course of vaccine (three doses) in 2014. To evaluate the potential impact of HPV vaccines in the reduction of HPV-related disease, we aimed to estimate the HPV type distribution and burden of anogenital and head and neck cancers attributable to HPV types (HPVs 16/18/31/33/45/52/58/6/11) included in currently licensed HPV vaccines. Methods In all, 18 247 formalin-fixed paraffin-embedded specimens were retrieved from 50 countries. HPV DNA detection and typing were performed with the SPF-10 PCR/DEIA/LiPA25 system. With the exception of cervical cancer, HPV DNA-positive samples were additionally subjected to HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. For cervical cancer, estimates were based on HPV DNA, whereas for other sites, estimates were based on HPV DNA, E6*I mRNA, and p16INK4a biomarkers. Results The addition of HPVs 31/33/45/52/58 to HPVs 16/18/6/11 in the nonavalent HPV vaccine could prevent almost 90% of cervical cancer cases worldwide. For other sites, the nonavalent HPV vaccine could prevent 22.8% of vulvar, 24.5% of penile, 60.7% of vaginal, 79.0% of anal cancers, 21.3% of oropharyngeal, 4.0% of oral cavity, and 2.7% of laryngeal cancer cases. Conclusions Our estimations suggest a potential impact of the nonavalent HPV vaccine in reducing around 90% of cervical cancer cases and a global reduction of 50% of all the cases at HPV-related cancer sites.

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An Overview of Innovative Techniques to Improve Cervical Cancer Screening

Analytical Cellular Pathology ◽

10.1155/2006/273547 ◽

2006 ◽

Vol 28 (5-6) ◽

pp. 233-246

Author(s):

Esther R. Nijhuis ◽

Nathalie Reesink-Peters ◽

G. Bea A. Wisman ◽

Hans W. Nijman ◽

Jelmer van Zanden ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Screening ◽

Cervical Cancer Screening ◽

Pap Smear ◽

New Technologies ◽

Dna Detection ◽

Screening Method ◽

Hpv Dna ◽

Screening Programs ◽

Current Screening

Although current cytomorphology-based cervical cancer screening has reduced the incidence of cervical cancer, Papsmears are associated with high false positive and false negative rates. This has spurred the search for new technologies to improve current screening. New methodologies are automation of Pap-smear analysis, addition of new biological or molecular markers to traditional cytology or using these new markers to replace the current screening method. In this overview we will summarize data on cervical cancer epidemiology and etiology and the current cervical cancer screening approach. Available data on new screening approaches, such as quantitative cytochemistry, detection of loss of heterozygosity (LOH) and hypermethylation analysis will be reviewed.We discuss the potential of these approaches to replace or augment current screening. When available, data on cost– effectiveness of certain approaches will be provided. In short, Human Papillomavirus (HPV) DNA detection stands closest to implementation in nation-wide screening programs of all markers reviewed. However, specificity is low in women aged <35 years and the psychological effects of knowledge of HPV positivity in absence of cervical (pre) malignant disease are important drawbacks. In our opinion the results of large clinical trials should be awaited before proceeding to implement HPV DNA detection. New technologies based on molecular changes associated with cervical carcinogenesis might result in comparable sensitivity, but improved specificity. Hypermethylation analysis is likely to be more objective to identify patients with high grade squamous intra-epithelial lesions (HSIL) or invasive cancer with a higher specificity than current cytomorphology based screening.

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Human Papillomavirus Selected Properties and Related Cervical Cancer Prevention Issues

Current Pharmaceutical Design ◽

10.2174/1381612826666200422094205 ◽

2020 ◽

Vol 26 (18) ◽

pp. 2073-2086

Author(s):

Saule Balmagambetova ◽

Andrea Tinelli ◽

Ospan A. Mynbaev ◽

Arip Koyshybaev ◽

Olzhas Urazayev ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Cancer Prevention ◽

Screening Program ◽

Hpv Infection ◽

Cervical Cancer Prevention ◽

Point Of View ◽

Prevention Strategies ◽

Middle Income ◽

Screening Programs

High-risk human papillomavirus strains are widely known to be the causative agents responsible for cervical cancer development. Aggregated damage caused by papillomaviruses solely is estimated in at least 5% of all malignancies of the human body and 16% in cancers that affect the female genital area. Enhanced understanding of the complex issue on how the high extent of carcinogenicity is eventually formed due to the infection by the Papoviridae family would contribute to enhancing current prevention strategies not only towards cervical cancer, but also other HPV associated cancers. This review article is aimed at presenting the key points in two directions: the current cervical cancer prevention and related aspects of HPV behavior. Virtually all applied technologies related to HPV diagnostics and screening programs, such as HPV tests, colposcopy-based tests (VIA/VILI), conventional and liquid-based cytology, currently available are presented. Issues of availability, advantages, and drawbacks of the screening programs, as well as vaccination strategies, are also reviewed in the article based on the analyzed sources. The current point of view regarding HPV is discussed with emphasis on the most problematic aspect of the HPV family concerning the observed increasing number of highly carcinogenic types. Present trends in HPV infection diagnostics throughout the human fluids and tissues are also reported, including the latest novelties in this field, such as HPV assay/self-sample device combinations. Besides, a brief outline of the related prevention issues in Kazakhstan, the leading country of Central Asia, is presented. Kazakhstan, as one of the post-soviet middle-income countries, may serve as an example of the current situation in those terrains, concerning the implementation of globally accepted cervical cancer prevention strategies. Along with positive achievements, such as the development of a nationwide screening program, a range of drawbacks is also analyzed and discussed.

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Effect of introducing human papillomavirus genotyping into real-world screening on cervical cancer screening in China: a retrospective population-based cohort study

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211010939 ◽

2021 ◽

Vol 13 ◽

pp. 175883592110109

Author(s):

Binhua Dong ◽

Huachun Zou ◽

Xiaodan Mao ◽

Yingying Su ◽

Hangjing Gao ◽

...

Keyword(s):

Cervical Cancer ◽

Cohort Study ◽

Human Papillomavirus ◽

Cancer Screening ◽

Cervical Cancer Screening ◽

Cox Regression ◽

Intraepithelial Neoplasia ◽

Population Based ◽

Hpv Genotyping ◽

Cytology Screening

Background: China’s Fujian Cervical Pilot Project (FCPP) transitioned cervical cancer screening from high-risk human papillomavirus (HR-HPV) nongenotyping to genotyping. We investigated the clinical impact of this introduction, comparing performance indicators between HR-HPV genotyping combined with cytology screening (HR-HPV genotyping period) and the previous HR-HPV nongenotyping combined with cytology screening (HR-HPV nongenotyping period). Methods: A retrospective population-based cohort study was performed using data from the FCPP for China. We obtained data for the HR-HPV nongenotyping period from 1 January 2012 to 31 December 2013, and for the HR-HPV genotyping period from 1 January 2014 to 31 December 2016. Propensity score matching was used to match women from the two periods. Multivariable Cox regression was used to assess factors associated with cervical intraepithelial neoplasia of grade 2 or worse (CIN2+). The primary outcome was the incidence of CIN2+ in women aged ⩾25 years. Performance was assessed and included consistency, reach, effectiveness, adoption, implementation and cost. Results: Compared with HR-HPV nongenotyping period, in the HR-HPV genotyping period, more CIN2+ cases were identified at the initial screening (3.06% versus 2.32%; p < 0.001); the rate of colposcopy referral was higher (10.87% versus 6.64%; p < 0.001); and the hazard ratio of CIN2+ diagnosis was 1.64 (95% confidence interval, 1.43–1.88; p < 0.001) after controlling for health insurance status and age. The total costs of the first round of screening (US$66,609 versus US$65,226; p = 0.293) were similar during the two periods. Higher screening coverage (25.95% versus 25.19%; p = 0.007), higher compliance with age recommendations (92.70% versus 91.69%; p = 0.001), lower over-screening (4.92% versus 10.15%; p < 0.001), and reduced unqualified samples (cytology: 1.48% versus 1.73%, p = 0.099; HR-HPV: 0.57% versus 1.34%, p < 0.001) were observed in the HR-HPV genotyping period. Conclusions: Introduction of an HR-HPV genotyping assay in China could detect more CIN2+ lesions at earlier stages and improve programmatic indicators. Evidence suggests that the introduction of HR-HPV genotyping is likely to accelerate the elimination of cervical cancer in China.

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Automated Quantitative Cytology Imaging Analysis System in Cervical Cancer Screening in Shanxi Province, China

Cancer and Clinical Oncology ◽

10.5539/cco.v6n2p51 ◽

2017 ◽

Vol 6 (2) ◽

pp. 51 ◽

Cited By ~ 1

Author(s):

Yan Dong ◽

Jigeng Bai ◽

Yuping Zhang ◽

Guangjie Shang ◽

Yan Zhao ◽

...

Keyword(s):

Artificial Intelligence ◽

Cervical Cancer ◽

Cancer Screening ◽

Cervical Cancer Screening ◽

Population Based ◽

Shanxi Province ◽

Detection Rates ◽

Screening Programs ◽

Quantitative Cytology ◽

Automated Platform

Purpose: In China the number of pathologists is far from being enough to meet the demands of ongoing population based cervical cancer screening programs. This article aims to present our experience with automated quantitative cytology imaging platform, a reading system with an artificial intelligence that we currently use routinely for cervical cancer screening in Shanxi province.Methods: From 2012-2016 a total of 40 178 women were screened. Women were divided into three groups and each group had two subgroups. Smear and liquid based technique were compared using manual and automated platform.Results: Detection rates of CIN2 + and positive rates of CIN2 were higher in all three groups when automated quantitative cytology platform was used compared with groups where reading was done by the pathologist using conventional microscope. Operator’s costs associated with automated quantitative cytology platform vs. conventional reading using light microscope were compared too. The overall costs of operations based on automated platform were proven to be lower.Conclusion: The use of automated platform and artificial intelligence as a means to overcome the lack of cytotechnologists and pathologists and to implement proper quality control in the large scale population based cervical cancer screening seems very promising.

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