Prediction of Human Papillomavirus 16 E6 Gene Expression and Cervical Intraepithelial Neoplasia Progression by Methylation Status

Introduction:Human papillomavirus (HPV) infection represents the most important risk factor for the development of cervical intraepithelial neoplasia (CIN) and cervical cancer. We aimed to analyze the consequences of methylation of the E6 gene promoter in distinct stages of HPV-16-induced cellular transformation to assess its importance for disease progression.Methods:Human papillomavirus 16 was detected by sensitive polymerase chain reaction (PCR). Determination of E6 gene promoter methylation was analyzed by digestion with specific restriction endonuclease McrBC followed by PCR amplification. Expression of the E6 gene was determined by quantitative real-time PCR.Results:Of 103 cervical smears from asymptomatic women with no cytological and colposcopic abnormalities, 20.4% were HPV-16-positive. Human papillomavirus 16 was present in 44.4% of 18 patients with CIN I, in 62.2% of 143 patients with CIN II/III, and in 74.2% of 31 cervix carcinoma specimens. The incidence of HPV-16 in all lesions compared with asymptomatic women was statistically significant (P< 0.001, Pearsonχ2test). Methylation was detected in 81% (n = 21) of HPV-16-positive asymptomatic smears compared with 62.5% in CIN I (n = 8), 31.5% (n = 89) in CIN II/III, and 43.4% (n = 23) in carcinomas; a statistical significance between lesions and healthy women was found (P< 0.001, Pearsonχ2test). Expression of E6 mRNA correlated with methylation status (P= 0.010, Mann-WhitneyUtest).Conclusions:We conclude that methylation of the E6 gene promoter in HPV-16 genome is a predictive biomarker for cervical cancer progression by regulating the expression of the E6 oncogene.

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PECULIARITIES OF PAPILLOMAVIRUS GENOTYPING IN PATIENTS WITH CERVICAL INTRAEPITHELIAL NEOPLASIA

Ulyanovsk Medico-biological Journal ◽

10.34014/2227-1848-2020-3-104-111 ◽

2020 ◽

pp. 104-111

Author(s):

N.A. Shmakova ◽

G.N. Chistyakova ◽

I.N. Kononova ◽

I.I. Remizova

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Viral Load ◽

Cervical Intraepithelial Neoplasia ◽

Intraepithelial Neoplasia ◽

Squamous Intraepithelial Lesions ◽

Hpv 16 ◽

The World ◽

Intraepithelial Lesions ◽

Hpv 18

Recently, there has been a steady growth of cervical cancer all over the world, especially in Russia. Patients with cervical cancer have become much younger. At the same time, the human papillomavirus is not only the main factor in the neoplastic process, but it is also one of the most common sexually transmitted infections in the world. The aim of the paper is to assess the prevalence and characteristics of human papillomavirus genotypes in patients with cervical intraepithelial neoplasia. Materials and Methods. During the periodic screening we examined 213 women of a reproductive age with HPV infection. All patients underwent liquid-based cytology and human papillomavirus genotyping by polymerase chain reaction. Results. We revealed that the prevalence of cervical intraepithelial neoplasia among women with papillomavirus infection was 80.3 % (n=171). According to human papillomavirus genotyping, HPV 16 (38 %) and HPV 33 (32 %) prevailed. We also observed positive high correlation between high-grade squamous intraepithelial lesions (HSIL) and HPV 18 (r=+0.759, p=0.001), a negative mean correlation between HPV 45 and low-grade squamous intraepithelial lesions (LSIL) (r=-0.643, p=0.002). A cohort of patients with severe intraepithelial cervical lesions demonstrated high viral load rates. Conclusion. According to the results obtained, we established the dominance of HPV 16 and HPV 33 genotypes in cervical intraepithelial neoplasia. There were significant differences between HSIL and LSIL patients with HPV 18 and HPV 45. There was also a correlation between an increase in the viral load with the severity of the pathological process. Keywords: human papillomavirus, intraepithelial cervical neoplasms, cervical cancer. В последние годы в мире, особенно в России, наблюдается неуклонный рост и «омолаживание» рака шейки матки. При этом вирус папилломы человека является не только основным фактором прогрессирования неопластического процесса, но и одной из наиболее распространенных инфекций, предаваемых половым путем, в мире. Цель. Оценить распространенность и характеристику генотипов папилломавирусной инфекции у пациенток с цервикальными интраэпителиальными неоплазиями. Материалы и методы. Проведено обследование 213 пациенток репродуктивного возраста с ВПЧ-инфекцией, пришедших на профилактический осмотр. Всем женщинам было выполнено цитологическое исследование жидкостным методом и генотипирование вируса папилломы человека методом полимеразной цепной реакции. Результаты. Распространенность цервикальных интраэпителиальных неоплазий среди женщин с папилломавирусной инфекцией составила 80,3 % (171 пациентка). Согласно данным генотипирования вируса папилломы человека превалировал 16-й (38 %) и 33-й типы (32 %). Выявлена положительная высокая корреляционная связь между цервикальными неоплазиями высокой степени онкогенного риска (HSIL) и 18-м типом ВПЧ-инфекции (r=+0,759 при р=0,001), отрицательная средняя корреляционная связь 45-го типа ВПЧ с низкой степенью онкогенного риска (LSIL) (r=-0,643 при р=0,002). Продемонстрированы высокие показатели вирусной нагрузки в когорте пациенток с тяжелыми внутриэпителиальными цервикальными поражениями. Выводы. По результатам полученных данных установлено доминирование 16-го и 33-го генотипов ВПЧ при цервикальных интраэпителиальных неоплазиях с наличием значимых различий между пациентами с HSIL и LSIL в отношении 18-го и 45-го типов, а также связь роста уровня вирусной нагрузки с увеличением степени тяжести патологического процесса. Ключевые слова: вирус папилломы человека, интраэпителиальные новообразования шейки матки, рак шейки матки.

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Serologic response to human papillomavirus 16 among Australian women with high-grade cervical intraepithelial neoplasia

International Journal of Gynecological Cancer ◽

10.1136/ijgc-00009577-200605000-00013 ◽

2006 ◽

Vol 16 (3) ◽

pp. 1032-1035

Author(s):

S. N. Tabrizi ◽

I. H. Frazer ◽

S. M. Garland

Keyword(s):

Human Papillomavirus ◽

Cervical Intraepithelial Neoplasia ◽

Intraepithelial Neoplasia ◽

High Grade ◽

Hpv 16 ◽

Hpv Dna ◽

Human Papillomavirus 16 ◽

Serologic Response ◽

Poor Predictor ◽

Hpv Types

This study evaluated the detection of human papillomavirus (HPV) 16 antibody in HPV 16–associated cervical intraepithelial neoplasia (CIN) in Australian women. Seroreactivity to HPV 16 L1 virus–like particles was assessed in patients with CIN 2 (n = 169) and CIN 3 (n = 229) lesions previously tested for the presence of HPV DNA. Seropositivity was significantly commoner in women with HPV 16 DNA–positive lesions (98/184) than in women with no HPV DNA in the lesion (15/47) or with HPV of types other than 16 in the lesion (43/167) (P = 0.0004). In addition, seropositivity was observed in 33% (55/169) of women with CIN 2 and 46% (106/229) of women with CIN 3, in keeping with the lower fraction of CIN 2 (57/169) than CIN 3 (127/229) biopsies positive for HPV 16 DNA. HPV 16 seropositivity is most common in women with HPV 16–associated CIN, but many patients with HPV-associated CIN 3 are seronegative, and HPV 16 seropositivity is common in women with CIN associated with other HPV types. Overall, HPV 16 serology is a poor predictor of presence of HPV 16–associated CIN 3 in patient population studied.

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Serologic Response to Human Papillomavirus Type 16 (HPV-16) Virus-like Particles in HPV-16 DNA-Positive Invasive Cervical Cancer and Cervical Intraepithelial Neoplasia Grade III Patients and Controls from Colombia and Spain

The Journal of Infectious Diseases ◽

10.1093/infdis/172.1.19 ◽

1995 ◽

Vol 172 (1) ◽

pp. 19-24 ◽

Cited By ~ 78

Author(s):

B. Nonnenmacher ◽

N. L. Hubbert ◽

R. Kirnbauer ◽

K. V. Shah ◽

N. Munoz ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Cervical Intraepithelial Neoplasia ◽

Invasive Cervical Cancer ◽

Intraepithelial Neoplasia ◽

Cervical Intraepithelial Neoplasia Grade ◽

Hpv 16 ◽

Human Papillomavirus Type 16 ◽

Serologic Response ◽

Grade Iii

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Human papillomavirus 16 and 18 L1 serology in Korean women with high-grade cervical intraepithelial neoplasia and cervical cancer

Archives of Pharmacal Research ◽

10.1007/s12272-009-1706-z ◽

2009 ◽

Vol 32 (7) ◽

pp. 1013-1018 ◽

Cited By ~ 6

Author(s):

Nan-Hee Jeong ◽

Mi-Kyung Woo ◽

Nak-Woo Lee ◽

Sook-Jin Hur ◽

Kum-Sook Choi ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Cervical Intraepithelial Neoplasia ◽

Intraepithelial Neoplasia ◽

High Grade ◽

Korean Women ◽

Human Papillomavirus 16

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Human Papillomavirus 16 lineage D is associated with high risk of cervical cancer in the Brazilian Northeast region

10.21203/rs.3.rs-1146588/v1 ◽

2021 ◽

Author(s):

Luís Felipe Leite Martins ◽

Miguel Ângelo Martins Moreira ◽

Rodrigo Alves Pinho ◽

Neilane Bertoni ◽

Shayany Pinto Felix ◽

...

Keyword(s):

Cervical Cancer ◽

Cervical Intraepithelial Neoplasia ◽

Intraepithelial Neoplasia ◽

P Value ◽

Histopathological Diagnosis ◽

Cross Sectional ◽

Hpv 16 ◽

Northeast Region ◽

Human Papillomavirus 16 ◽

Cancer Group

Abstract BackgroundLike HPV types, different lineages also appear to have different carcinogenic capabilities. Studies have shown that oncogenic HPV specific to the genotype lineage is associated with different risks for the development of cervical intraepithelial neoplasia (CIN2 / CIN3) and cervical cancer. This study aims to analyze the genetic diversity of HPV 16 genotype in cases of cervical intraepithelial neoplasia (CIN2/CIN3) and cervical cancer in women from the Northeast region of Brazil.Methods and ResultsA cross-sectional hospital-based study conducted in the Northeast region of Brazil from 2014 through 2016. In the sample, there were 196 cases of HPV-16 variant (59 cervical intraepithelial neoplasia - CIN2/CIN3 and 137 cases of cervical cancer). Difference of proportion test was used to compare groups of CIN2/CIN3 and cervical cancer by viral lineage (p-value <0.05) in respect to HPV-16 lineage prevalence.The percentage of lineage frequencies by histopathological diagnosis showed a borderline difference of lineage A in the CIN2/CIN3 group compared to the cervical cancer group (p = 0.053). In relation to lineage D, the proportion was higher in cancer cases (32.8%) compared to the CIN2/CIN3 group (16.9%), p-value of 0.023.ConclusionsHPV16 lineage A was the most frequent in both CIN2/CIN3 and cervical cancer samples, while lineage D predominated in cervical cancer, suggesting a possible association of HPV-16 lineage D with cervical cancer.

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Human Papillomavirus Type Distribution in Cervical Intraepithelial Neoplasia Grade 2/3 and Cervical Cancer in Portugal: A CLEOPATRE II Study

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e318280f26e ◽

2013 ◽

Vol 23 (3) ◽

pp. 500-506 ◽

Cited By ~ 13

Author(s):

Angela Pista ◽

Carlos Freire de Oliveira ◽

Carlos Lopes ◽

Maria João Cunha

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

High Risk ◽

Cervical Intraepithelial Neoplasia ◽

Invasive Cervical Cancer ◽

Intraepithelial Neoplasia ◽

Multiple Infections ◽

Hpv 16 ◽

Specific Distribution ◽

Hpv Genotypes

ObjectiveCervical cancer is the third most frequent cancer in women, worldwide and etiologically associated with infection by human papillomavirus (HPV). Following the results of the first epidemiologic population-based CLEOPATRE study in Portugal, it was important to understand the HPV type-specific distribution in women with cervical intraepithelial neoplasia (CIN) grades 2 and 3 and invasive cervical cancer (ICC).MethodsThis was an observational, multicenter, cross-sectional study with retrospective data collection. Between January 2008 and May 2009, paraffin-embedded samples of histologically confirmed cases of CIN2, CIN3, and ICC were collected from the 5 regional health administrations in mainland Portugal. Eligible samples were sent to 2 central laboratories for histological reassessment and HPV genotyping. Prevalence estimates were calculated together with 95% confidence intervals.ResultsA total of 582 samples, 177 cases of CIN2, 341 of CIN3, and 64 of ICC, were included. The mean age of participants was 41.8 years (range, 20–88 years). The overall HPV prevalence was 97.9% with a higher prevalence of high-risk genotypes, particularly HPV 16. Multiple infections were observed in 11.2% of the cases. Human papillomavirus prevalence was 95.5% in CIN2, 99.4% in CIN3, and 96.9% in ICC. The 8 more frequent genotypes in order of decreasing frequency were HPV 16, 31, 58, 33, 51, 52, 18, and 35 in CIN2 and HPV 16, 31, 33, 58, 52, 35, 18, and 51 in CIN3. In ICC cases, the 12 detected HPV genotypes were HPV 16, 18, 31, 33, 45, 51, 52, 53, 56, 58, 59, and 73. However, HPV 53 and 73 were always associated to other high-risk genotypes. Human papillomavirus types 31, 51, 52, 56, and 59 were detected in 1 case each.ConclusionsHuman papillomavirus prevalence and patterns of type-specific HPV positivity were comparable with other studies. Current HPV vaccines should protect against HPV genotypes responsible for 77.4% of ICC in Portugal.

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Ten-year follow-up of human papillomavirus vaccine efficacy against the most stringent cervical neoplasia end-point—registry-based follow-up ofthree cohorts from randomized trials

BMJ Open ◽

10.1136/bmjopen-2017-015867 ◽

2017 ◽

Vol 7 (8) ◽

pp. e015867 ◽

Cited By ~ 33

Author(s):

Matti Lehtinen ◽

Camilla Lagheden ◽

Tapio Luostarinen ◽

Tiina Eriksson ◽

Dan Apter ◽

...

Keyword(s):

Human Papillomavirus ◽

Cervical Intraepithelial Neoplasia ◽

Cancer Registry ◽

Vaccine Efficacy ◽

Invasive Cervical Cancer ◽

Intraepithelial Neoplasia ◽

Cervical Intraepithelial Neoplasia Grade ◽

Hpv 16 ◽

Link Type

ObjectiveDue to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+).MethodsWe report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials’ end.ResultsDuring the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88).ConclusionsTen years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects.Trial registration numberNCT01393470.

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