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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Human papillomavirus (HPV) is the carcinogen of almost all invasive cervical cancer and a major cause of oral and other anogenital malignancies. HPV genotyping by dideoxy (Sanger) sequencing is currently the reference method of choice for clinical diagnostics. However, for samples with multiple HPV infections, genotype identification is singular and occasionally imprecise or indeterminable due to overlapping chromatograms. Our aim was to explore and compare HPV metagenomes in abnormal cervical cytology by deep sequencing for correlation with disease states.

Results

Low- and high-grade intraepithelial lesion (LSIL and HSIL) cytology samples were DNA extracted for PCR-amplification of the HPV E6/E7 genes. HPV+ samples were sequenced by dideoxy and deep methods. Deep sequencing revealed ~60% of all samples ( n = 72) were multi-HPV infected. Among LSIL samples ( n = 43), 27 different genotypes were found. The 3 dominant (most abundant) genotypes were: HPV-39, 11/43 (26%); -16, 9/43 (21%); and -35, 4/43 (9%). Among HSIL ( n = 29), 17 HPV genotypes were identified; the 3 dominant genotypes were: HPV-16, 21/29 (72%); -35, 4/29 (14%); and -39, 3/29 (10%). Phylogenetically, type-specific E6/E7 genetic distances correlated with carcinogenic potential. Species diversity analysis between LSIL and HSIL revealed loss of HPV diversity and domination by HPV-16 in HSIL samples.

Conclusions

Deep sequencing resolves HPV genotype composition within multi-infected cervical cytology. Biodiversity analysis reveals loss of diversity and gain of dominance by carcinogenic genotypes in high-grade cytology. Metagenomic profiles may therefore serve as a biomarker of disease severity and a population surveillance tool for emerging genotypes.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-017-3612-y) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 39

Record: found
Abstract: found
Article: not found

High-throughput sequencing technologies.

Jason A. Reuter, Damek Spacek, Michael Snyder (2015)

The human genome sequence has profoundly altered our understanding of biology, human diversity, and disease. The path from the first draft sequence to our nascent era of personal genomes and genomic medicine has been made possible only because of the extraordinary advancements in DNA sequencing technologies over the past 10 years. Here, we discuss commonly used high-throughput sequencing platforms, the growing array of sequencing assays developed around them, as well as the challenges facing current sequencing platforms and their clinical application. Copyright © 2015 Elsevier Inc. All rights reserved.

0 comments Cited 420 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.

Anne M. Johnson, Erich V. Kliewer, Louise Baandrup … (2015)

Human papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations. We searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random-effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I(2) and χ(2) statistics and we did trends analysis to examine the dose-response association between HPV vaccination coverage and each study effect measure. We identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow-up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post-vaccination periods by 68% (RR 0·32, 95% CI 0·19-0·52) and anogenital warts decreased significantly by 61% (0·39, 0·22-0·71) in girls 13-19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0·72, 95% CI 0·54-0·96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0·66 [95% CI 0·47-0·91]) and in women 20-39 years of age (0·68 [95% CI 0·51-0·89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0·50, 95% CI 0·34-0·74]) and in anogenital warts (0·86 [95% CI 0·79-0·94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects. Our results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement. The Canadian Institutes of Health Research. Copyright © 2015 Elsevier Ltd. All rights reserved.

0 comments Cited 243 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline

Mark Schiffman, Gary Clifford, Franco M Buonaguro (2009)

Virtually all cases of cervical cancer are caused by persistent infections with a restricted set of human papillomaviruses (HPV). Some HPV types, like HPV16 and HPV18, are clear and powerful carcinogens. However, the categorization of the most weakly carcinogenic HPV types is extremely challenging. The decisions are important for screening test and vaccine development. This article describes for open discussion an approach recently taken by a World Health Organization International Agency for Research on Cancer (IARC) Monographs Working Group to re-assess the carcinogenicity of different HPV types.

0 comments Cited 132 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Jane Shen-Gunther:

ORCID: http://orcid.org/0000-0002-0876-9338

(210) 916-2444 , jane.shengunther.mil@mail.mil

Yufeng Wang: yufeng.wang@utsa.edu

Zhao Lai: laiZ@uthscsa.edu

Graham M. Poage: gpoage00@yahoo.com

Luis Perez: luis.e.perez66.civ@mail.mil

Tim H. M. Huang: huangt3@uthscsa.edu

Journal

Journal ID (nlm-ta): BMC Genomics

Journal ID (iso-abbrev): BMC Genomics

Title: BMC Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2164

Publication date (Electronic): 14 March 2017

Publication date PMC-release: 14 March 2017

Publication date Collection: 2017

Volume: 18

Electronic Location Identifier: 231

Affiliations

[1 ]Department of Clinical Investigation, Brooke Army Medical Center, Gynecologic Oncology & Clinical Investigation, 3698 Chambers Pass, Fort Sam Houston, TX 78234 USA

[2 ]ISNI 0000000121845633, GRID grid.215352.2, Department of Biology, , University of Texas at San Antonio, ; San Antonio, TX 78249 USA

[3 ]ISNI 0000 0001 0629 5880, GRID grid.267309.9, , Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, ; San Antonio, TX 78229 USA

[4 ]ISNI 0000 0001 0629 5880, GRID grid.267309.9, Department of Molecular Medicine, , Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, ; San Antonio, TX 78229 USA

Author information

Jane Shen-Gunther http://orcid.org/0000-0002-0876-9338

Article

Publisher ID: 3612

DOI: 10.1186/s12864-017-3612-y

PMC ID: 5348809

PubMed ID: 28288568

SO-VID: f1b659c4-1afb-466a-8e3f-f6003a0d5b47

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 19 December 2016

Date accepted : 7 March 2017

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: human papillomavirus,hpv genotyping,high-throughput sequencing,deep sequencing,metagenome,virome,lsil,hsil

Data availability:

ScienceOpen disciplines: Genetics

Keywords: human papillomavirus, hpv genotyping, high-throughput sequencing, deep sequencing, metagenome, virome, lsil, hsil

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

Read this article at

Abstract

Background

Results

Conclusions

Electronic supplementary material

Related collections

Genome Integrity

Most cited references 39

High-throughput sequencing technologies.

Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.

Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 56

Cited by 14

Most referenced authors 1,021