Human Papillomavirus Genomics: Past, Present and Future

Harari, Ariana; Chen, Zigui; Burk, Robert D.

doi:10.1159/000355952

Cited by 67 publications

(58 citation statements)

References 82 publications

(115 reference statements)

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“…On the other hand, the topologies of the trees constructed with each of the nine individual ORFs and the URR were dichotomous, clearly identifying lineages A and B but poorly resolving sublineages A1 to A4. These observations further support the established concept of complete genome sequencing for the basis of HPV variant classification (42,46). Because nucleotide changes specific to genetic (sub)lineages are not evenly dispersed throughout the HPV genome, the generation of phylogenetic trees with sequences from individual genomic regions may result in trees with different topologies.…”

Section: Discussionsupporting

confidence: 66%

“…Because nucleotide changes specific to genetic (sub)lineages are not evenly dispersed throughout the HPV genome, the generation of phylogenetic trees with sequences from individual genomic regions may result in trees with different topologies. Therefore, only stable (sub)lineage-specific SNPs could serve as diagnostic sites in studies in which complete genome sequences cannot be obtained (26,42,46). In this study, following the identification of several (sub)lineage-specific SNPs, the most suitable genomic region (208 bp) for HPV11 whole-genome tree reconstruction and the identification of all currently known vari- ant (sub)lineages was found at the 3= end of the E2 ORF and the 5= end of NCR2.…”

Section: Discussionmentioning

confidence: 99%

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Global Genomic Diversity of Human Papillomavirus 11 Based on 433 Isolates and 78 Complete Genome Sequences

Jelen

Chen

Kocjan

et al. 2016

J Virol

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Human papillomavirus 11 (HPV11) is an etiological agent of anogenital warts and laryngeal papillomas and is included in the 4-valent and 9-valent prophylactic HPV vaccines. We established the largest collection of globally circulating HPV11 isolates to date and examined the genomic diversity of 433 isolates and 78 complete genomes (CGs) from six continents. The genomic variation within the 2,800-bp E5a-E5b-L1-upstream regulatory region was initially studied in 181/207 (87.4%) HPV11 isolates collected for this study. Of these, the CGs of 30 HPV11 variants containing unique single nucleotide polymorphisms (SNPs), indels (insertions or deletions), or amino acid changes were fully sequenced. A maximum likelihood tree based on the global alignment of 78 HPV11 CGs (30 CGs from our study and 48 CGs from GenBank) revealed two HPV11 lineages (lineages A and B) and four sublineages (sublineages A1, A2, A3, and A4). HPV11 (sub)lineage-specific SNPs within the CG were identified, as well as the 208-bp representative region for CG-based phylogenetic clustering within the partial E2 open reading frame and noncoding region 2. Globally, sublineage A2 was the most prevalent, followed by sublineages A1, A3, and A4 and lineage B. IMPORTANCEThis collaborative international study defined the global heterogeneity of HPV11 and established the largest collection of globally circulating HPV11 genomic variants to date. Thirty novel complete HPV11 genomes were determined and submitted to the available sequence repositories. Global phylogenetic analysis revealed two HPV11 variant lineages and four sublineages. The HPV11 (sub)lineage-specific SNPs and the representative region identified within the partial genomic region E2/noncoding region 2 (NCR2) will enable the simpler identification and comparison of HPV11 variants worldwide. This study provides an important knowledge base for HPV11 for future studies in HPV epidemiology, evolution, pathogenicity, prevention, and molecular assay development. Human papillomavirus 11 (HPV11), which belongs to species 10 of the Alphapapillomavirus genus (Alpha-PV), is etiologically associated with approximately 20% of anogenital warts and 30 to 40% of laryngeal papillomas (1-11). HPV11 is generally considered a low-risk HPV type due to its rare presence in HPVrelated cancers in humans, especially cervical cancer (9). HPV11 is present in 0.5% of samples from HPV-positive women with a normal cytology worldwide and causes 2.3% of cervical low-grade squamous cell intraepithelial lesions (12, 13). However, rare case reports of HPV11-positive cases of cervical and anal squamous cell carcinomas, malignantly transformed laryngeal papillomas, and sinonasal inverted papillomas associated with squamous cell carcinoma can be found in the literature (14-21). Due to its clinical significance, HPV11 has been included in the current quadrivalent and nonavalent prophylactic HPV vaccines (22,23).The genetic diversity of HPV11 was studied for the first time in 1995, when Heinzel et al. sequenced the noncoding upstre...

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Global Genomic Diversity of Human Papillomavirus 11 Based on 433 Isolates and 78 Complete Genome Sequences

Jelen

Chen

Kocjan

et al. 2016

J Virol

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“…The identification of carcinogenic HPVs in cervical lesion biopsies and exfoliated cells have evolved from restriction endonuclease cleavage patterns and DNA-DNA hybridization techniques to PCR-based systems [33] and most recently next-generation sequencing (NGS) assays [34]. Initially, techniques such as in situ hybridization or Southern blotting used radioactive probe-labeled nucleic acid hybridization to detect the presence of HPV DNA, providing high-quality data although technically demanding, time-consuming, and with lower sensitivity.…”

Section: Historical Overview Of Hpv Typingmentioning

confidence: 99%

“…The most recent advances in DNA NGS sequencing technologies have the potential to contribute to a better and deeper knowledge of HPV biology; improve viral detection and identification; expand the characterization of mechanisms associated with cervical malignancy; and perhaps facilitate new therapy development [44–46]. Likewise, understanding the molecular interactions present in the unique viral-host milieu within a patient by novel assays should enhance development of treatments and/or therapies that will have beneficial implications in fighting cervical cancer worldwide [33]. Additionally, initial studies of HPV epigenetics using methylation-specific restriction endonuclease patterns showed a correlation between increased CpG site methylation levels and high-grade cervical lesions and have evolved into more quantitative assays of CpG methylation [47].…”

Section: Historical Overview Of Hpv Typingmentioning

confidence: 99%

“…Additionally, initial studies of HPV epigenetics using methylation-specific restriction endonuclease patterns showed a correlation between increased CpG site methylation levels and high-grade cervical lesions and have evolved into more quantitative assays of CpG methylation [47]. More recent studies indicate that NGS assays can provide single molecule CpG methylation levels to help unravel the physiological role of methylation in cervical cancer development [33,47], as discussed below.…”

Section: Historical Overview Of Hpv Typingmentioning

confidence: 99%

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Molecular tests potentially improving HPV screening and genotyping for cervical cancer prevention

Gradíssimo

Burk

2017

Expert Review of Molecular Diagnostics

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INTRODUCTION Human papillomavirus (HPV)-related cancers can be averted by type-specific vaccination (primary prevention) and/or through detection and ablation of precancerous cervical lesions (secondary prevention). This review presents current challenges to cervical cancer screening programs, focusing on recent molecular advances in HPV testing and potential improvements on risk stratification. AREAS COVERED High-risk (HR)-HPV DNA detection has been progressively incorporated into cervix cancer prevention programs based on its increased sensitivity. Advances in next-generation sequencing (NGS) are being rapidly applied to HPV typing. However, current HPV DNA tests lack specificity for identification of cervical precancer (CIN3). HPV typing methods were reviewed based on published literature, with a focus on these applications for screening and risk stratification in the emerging complex clinical scenario post-vaccine introduction. In addition, the potential for NGS technologies to increase specificity is discussed in regards to reflex testing of specimens for emerging biomarkers for cervix precancer/cancer. EXPERT COMMENTARY Integrative multi-disciplinary molecular tests accurately triaging exfoliated cervical specimens will improve cervical cancer prevention programs while simplifying healthcare procedures in HPV-infected women. Hence, the concept of a “liquid-biopsy” (i.e., “molecular” Pap test) highly specific for early identification of cervical precancerous lesions is of critical importance in the years to come.

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