Deep sequencing of HPV E6/E7 genes reveals loss of genotypic diversity and gain of clonal dominance in high-grade intraepithelial lesions of the cervix

Shen-Gunther, Jane; Wang, Yufeng; Lai, Zhao; Poage, Graham M.; Pérez, Luis E.; Huang, Tim Hui-Ming

doi:10.1186/s12864-017-3612-y

Cited by 23 publications

(35 citation statements)

References 44 publications

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“…Although Sanger sequencing is still the gold standard, it lacks the resolution generated by next-generation sequencing (NGS) techniques. Only the major variant driving the infection can be reliably determined, and any coinfections present in the samples cannot be reliably identified ( 15 ). On the other hand, major variants have been implicated in causing persistent infections, while minor variants appear more transient in nature ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing and Variant Analysis of Human Papillomavirus 16 Infections

Weele

Meijer²,

King

2017

J Virol

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Human papillomavirus (HPV) is a strongly conserved DNA virus, high-risk types of which can cause cervical cancer in persistent infections. The most common type found in HPV-attributable cancer is HPV16, which can be subdivided into four lineages (A to D) with different carcinogenic properties. Studies have shown HPV16 sequence diversity in different geographical areas, but only limited information is available regarding HPV16 diversity within a population, especially at the whole-genome level. We analyzed HPV16 major variant diversity and conservation in persistent infections and performed a single nucleotide polymorphism (SNP) comparison between persistent and clearing infections. Materials were obtained in the Netherlands from a cohort study with longitudinal follow-up for up to 3 years. Our analysis shows a remarkably large variant diversity in the population. Whole-genome sequences were obtained for 57 persistent and 59 clearing HPV16 infections, resulting in 109 unique variants. Interestingly, persistent infections were completely conserved through time. One reinfection event was identified where the initial and follow-up samples clustered differently. Non-A1/A2 variants seemed to clear preferentially (P = 0.02). Our analysis shows that population-wide HPV16 sequence diversity is very large. In persistent infections, the HPV16 sequence was fully conserved. Sequencing can identify HPV16 reinfections, although occurrence is rare. SNP comparison identified no strongly acting effect of the viral genome affecting HPV16 infection clearance or persistence in up to 3 years of follow-up. These findings suggest the progression of an early HPV16 infection could be host related.IMPORTANCE Human papillomavirus 16 (HPV16) is the predominant type found in cervical cancer. Progression of initial infection to cervical cancer has been linked to sequence properties; however, knowledge of variants circulating in European populations, especially with longitudinal follow-up, is limited. By sequencing a number of infections with known follow-up for up to 3 years, we gained initial insights into the genetic diversity of HPV16 and the effects of the viral genome on the persistence of infections. A SNP comparison between sequences obtained from clearing and persistent infections did not identify strongly acting DNA variations responsible for these infection outcomes. In addition, we identified an HPV16 reinfection event where sequencing of initial and follow-up samples showed different HPV16 variants. Based on conventional genotyping, this infection would incorrectly be considered a persistent HPV16 infection. In the context of vaccine efficacy and monitoring studies, such infections could potentially cause reduced reported efficacy or efficiency.

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Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing and Variant Analysis of Human Papillomavirus 16 Infections

Weele

Meijer²,

King

2017

J Virol

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“…An interesting result is that men with multiple HPV types had a significant higher risk of an abnormal cytological finding as compared to men with single HPV infection even in the absence of with HPV 16. A recent study by Shen-Gunter et al [ 17 ] analyzed the HPV genotypes and their proportional composition in single- and multi-infected cervical samples to explore viral diversity and characterize differences in metagenomes. They identified in LSIL/HSIL samples many HPV genotypes and the dominant(most abundant) genotypes mainly included the HPV-16 genotype; the other observed genotypes were the HPV-35 and -39.…”

Section: Discussionmentioning

confidence: 99%

“…With respect to the diagnosis of AIDS, previous data showed that it is a risk factor for SIL [ 4 , 17 ]; Goedert and colleagues [ 19 ], reported that the relative risk of HSIL development is 31.7 after the diagnosis of AIDS.…”

Section: Discussionmentioning

confidence: 99%

Presence of multiple genotypes in subjects with HPV-16 infection is highly associated with anal squamous intraepithelial lesions in HIV-1 infected males

et al. 2017

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ObjectivesThe aim of the study was to determine the prevalence of abnormal cytological findings, high risk (HR)-HPV genotypes and to identify factors associated with an abnormal cytological findings in a cohort of HIV-infected males.Patients and methodsRetrospective observational study on HIV-infected male patients who performed screening in the absence of clinical symptoms. Cytological abnormalities were classified as atypical squamous cells of undetermined significance (ASC-US), low-grade(LSIL) or high high-grade squamous intraepithelial lesion (HSIL). Logistic regression models were used to identify predictors of having LSIL/HSIL.ResultsAmong 875 pts, abnormal cytology findings were observed in 254 (29%, 95% CI: 26.1%-32.1%) subjects: 142 (16%) had LSIL and 49 (6%) HSIL. Overall, 581 (66%, 95%CI: 63.2%-69.5%) subjects had ≥1 HR-HPV type and 269 (31%) had ≥2 HR HPV types. Multivariate logistic regression showed that subjects with multiple HR-HPV genotypes (OR = 1.351, 95%CI: 1.005–2.111) and with HPV-16 type (OR = 2.032, 95%CI: 1.313–3.146) were more likely to have LSIL/HSIL in addition to a lower CD4+/CD8+ ratio, a previous diagnosis of syphilis and a positive viral load. In another multivariate model, the presence of multiple HPV types in subjects with HPV-16 type was associated with the highest adjusted OR of having a LSIL/HSIL (OR = 2.598, 95%CI: 1.460–4.624).ConclusionsIn HIV-infected men, the prevalence of abnormal cytological findings was of 29% and of HR-HPV was 66%. The concomitant presence of HPV-16 and multiple HR genotypes was associated with an increased risk of abnormal cytological findings.These data highlight the importance of screening multiple HPV genotypes in HIV-infected patients.

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“…In fact recent studies performing deep sequencing of HPV E6/E7 genes have revealed loss of genotypic diversity and clonal dominance in high-grade intraepithelial lesions of the cervix. The differences in carcinogenic potential among various HPV genotypes are related tothe evolutionary distances between HPV species (measured using HPV L1 or E6/7 genes) which correlate with the level of IARC-defined carcinogenicity [ 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

Predictors of abnormal cytology among HPV-infected women in remote territories of French Guiana

et al. 2018

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BackgroundCervical cancer prevention using cervical cytology is insufficiently sensitive, a significant proportion of HPV-infected women having normal cytology.The objective of the present study was to try to identify factors associated with abnormal cytology in HPV-infected women living in remote areas of French Guiana.MethodsA study was conducted in women aged 20–65 years having HPV infections confirmed by HPV DNA detection using the GREINER-BIO-ONE kit. In addition to HPV testing, cytology was performed and classified as normal or abnormal. Demographic and life history variables, and infecting genotypes were compared between the normal and abnormal cytology groups.ResultsNone of the demographic and life history variables were associated with cytology results. HPV genotype 53 was significantly associated with absence of cytological abnormalities whereas HPV 52, 58, 16 and perhaps 33 and 66 were independently associated with a greater risk of cytological abnormalities. When grouping HPV genotypes in different species, only species 9 (HPV 16, 31, 33, 35, 52, 58, 67) was significantly associated with abnormal cytology AOR = 5.1 (95% CI = 2.3–11.2), P < 0.001.ConclusionsIt was not possible to predict which HPV-infected women will have cytological abnormalities or notfrom anamnesis. In this study HPV 53 seemed more benign than other HPV genotypes. On the contrary, species n°9, containing 5 of the genotypes contained in the nonavalent HPV vaccine, was significantly associated with more cytological abnormalities. HPV testing and vaccination with the nonavalent vaccine should be implemented in these remote parts of French Guiana.

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Deep sequencing of HPV E6/E7 genes reveals loss of genotypic diversity and gain of clonal dominance in high-grade intraepithelial lesions of the cervix

Cited by 23 publications

References 44 publications

Whole-Genome Sequencing and Variant Analysis of Human Papillomavirus 16 Infections

Whole-Genome Sequencing and Variant Analysis of Human Papillomavirus 16 Infections

Presence of multiple genotypes in subjects with HPV-16 infection is highly associated with anal squamous intraepithelial lesions in HIV-1 infected males

Predictors of abnormal cytology among HPV-infected women in remote territories of French Guiana

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