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Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women.

ABSTRACT: BACKGROUND:Human papillomavirus (HPV)16 can be separated into genetic sub-lineages (A1-4, B1-4, C1-4, D1-4) which may have differential cervical cancer risk. METHODS:A next-generation sequencing assay was used to whole-genome sequence 7116 HPV16-positive cervical samples from well-characterised international epidemiological studies, including 2076 controls, 1878 squamous cell carcinoma (SCC) and 186 adenocarcinoma/adenosquamous cell carcinoma (ADC), and to assign HPV16 sub-lineage. Logistic regression was used to estimate region-stratified country-adjusted odds ratios (OR) and 95%CI. RESULTS:A1 was the most globally widespread sub-lineage, with others showing stronger regional specificity (A3 and A4 for East Asia, B1-4 and C1-4 for Africa, D2 for the Americas, B4, C4 and D4 for North Africa). Increased cancer risks versus A1 were seen for A3, A4 and D (sub)lineages in regions where they were common: A3 in East Asia (OR=2.2, 95%CI:1.0-4.7); A4 in East Asia (6.6, 3.1-14.1) and North America (3.8, 1.7-8.3); and D in North (6.2, 4.1-9.3) and South/Central America (2.2, 0.8-5.7), where D lineages were also more frequent in ADC than SCC (3.2, 1.5-6.5; 12.1, 5.7-25.6, respectively). CONCLUSIONS:HPV16 genetic variation can strongly influence cervical cancer risk. However, burden of cervical cancer attributable to different sub-lineages worldwide is largely driven by historical HPV16 sub-lineage dispersal.

SUBMITTER: Clifford GM

PROVIDER: S-EPMC6374642 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women.

Clifford Gary M GM Tenet Vanessa V Georges Damien D Alemany Laia L Pavón Miquel Angel MA Chen Zigui Z Yeager Meredith M Cullen Michael M Boland Joseph F JF Bass Sara S Steinberg Mia M Raine-Bennett Tina T Lorey Thomas T Wentzensen Nicolas N Walker Joan J Zuna Rosemary R Schiffman Mark M Mirabello Lisa L

Papillomavirus research (Amsterdam, Netherlands) 20190206

<h4>Background</h4>Human papillomavirus (HPV)16 can be separated into genetic sub-lineages (A1-4, B1-4, C1-4, D1-4) which may have differential cervical cancer risk.<h4>Methods</h4>A next-generation sequencing assay was used to whole-genome sequence 7116 HPV16-positive cervical samples from well-characterised international epidemiological studies, including 2076 controls, 1878 squamous cell carcinoma (SCC) and 186 adenocarcinoma/adenosquamous cell carcinoma (ADC), and to assign HPV16 sub-lineage ...[more]

PMID: 30738204

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Project description:BackgroundPersistent infection with oncogenic Human Papillomavirus (HPV) is associated with the development of cervical cancer with each genotype differing in their relative contribution to the prevalence of cervical disease. HPV DNA testing offers improved sensitivity over cytology testing alone but is accompanied by a generally low specificity. Potential molecular markers of cervical disease include type-specific viral load (VL), integration of HPV DNA into the host genome and methylation of the HPV genome. The aim of this study was to evaluate the relationship between HPV type-specific viral load, integration and methylation status and cervical disease stage in samples harboring HPV16, HPV18, HPV31 or HPV45.MethodsSamples singly infected with HPV16 (n=226), HPV18 (n=32), HPV31 (n=75) or HPV45 (n=29) were selected from a cohort of 4,719 women attending cervical screening in England. Viral load and integration status were determined by real-time PCR while 3'L1-URR methylation status was determined by pyrosequencing or sequencing of multiple clones derived from each sample.ResultsViral load could differentiate between normal and abnormal cytology with a sensitivity of 75% and a specificity of 80% (odds ratio [OR] 12.4, 95% CI 6.2-26.1; p<0.001) with some variation between genotypes. Viral integration was poorly associated with cervical disease. Few samples had fully integrated genomes and these could be found throughout the course of disease. Overall, integration status could distinguish between normal and abnormal cytology with a sensitivity of 72% and a specificity of 50% (OR 2.6, 95% CI 1.0-6.8; p=0.054). Methylation levels were able to differentiate normal and low grade cytology from high grade cytology with a sensitivity of 64% and a specificity of 82% (OR 8.2, 95% CI 3.8-18.0; p<0.001). However, methylation varied widely between genotypes with HPV18 and HPV45 exhibiting a broader degree and higher magnitude of methylated CpG sites than HPV16 and HPV31.ConclusionsThis study lends support for HPV viral load and CpG methylation status, but not integration status, to be considered as potential biomarkers of cervical disease.

Dataset Information

Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women.

Publications

Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women.

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