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Cancer Epidemiol Biomarkers Prev. 2018 Dec;27(12):1407-1415. doi: 10.1158/1055-9965.EPI-17-1051. Epub 2018 Sep 20.

Methylation of High-Risk Human Papillomavirus Genomes Are Associated with Cervical Precancer in HIV-Positive Women.

Author information

1
Department of Pediatrics (Genetic Medicine), Albert Einstein College of Medicine, Bronx, New York.
2
Department of Medicine (Infectious Disease), University of California, San Francisco, California.
3
Department of Obstetrics & Gynecology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
4
Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York.
5
Department of Pathology, University of Alabama, Birmingham, Alabama.
6
Department of Obstetrics & Gynecology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
7
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
8
Department of Medicine (Infectious Disease), Montefiore Medical Center, Bronx, New York.
9
Department of Obstetrics & Gynecology, Maimonides Medical Center, Brooklyn, New York.
10
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.
11
Department of Obstetrics & Gynecology, Emory University, Atlanta, Georgia.
12
Department of Obstetrics & Gynecology, Georgetown University, Washington, D.C.
13
Department of Epidemiology, University of Alabama, Birmingham, Alabama.
14
Departments of Clinical Pharmacy and Medicine, University of California, San Francisco, California.
15
Department of Pediatrics (Genetic Medicine), Albert Einstein College of Medicine, Bronx, New York. robert.burk@einstein.yu.edu.
16
Departments of Microbiology & Immunology, Epidemiology & Population Health, and Obstetrics, Gynecology & Women's Health, Albert Einstein College of Medicine, Bronx, New York.
#
Contributed equally

Abstract

BACKGROUND:

HIV-positive women are at substantial risk of HPV-associated cervical neoplasia caused by high-risk (HR) HPVs. Methylation of the HPV genome is associated with cervical intraepithelial neoplasia grade 3 (CIN3) in HIV-negative women, yet it is unknown whether this holds true for HIV-positive women.

METHODS:

We designed a case-control study within the Women's Interagency HIV Study (WIHS) cohort comparing HIV-positive CIN3 cases (N = 72) to HIV-positive controls without detectable CIN2+. The unit of analysis and matching was HPV-type infection. Cases with ≥2 HR-HPV types (N = 23; 32%) had a separate control for each HR-HPV type. We developed and utilized next-generation sequencing (NGS) methylation assays for 12 different HR-HPVs, focusing on CpG sites in the L1/L2 regions.

RESULTS:

Significant case-control differences in individual CpG site methylation levels were observed for multiple alpha-9 (HPV16/31/35/58) and alpha-7 HPV (HPV18/39/45) types, based on dichotomization of tertile levels (T3 vs. T1 and T2). Analyses combining homologous CpG sites [e.g., HPV16-L1-5608/HPV31-L1-5521/HPV35-L2L1-5570; OR = 7.28; 95% confidence interval (CI): 2.75-19.3], and (e.g., HPV18-L1-7062/HPV45-L1-7066; OR = 6.94; 95% CI: 1.23-39.3) were significant in separate case-control comparisons. In cases with multiple HR-HPVs, we tested and confirmed the hypothesis that one HR-HPV type would have higher methylation than other types detected, consistent with there being a single HR-HPV causally related to a lesion.

CONCLUSIONS:

CIN3 is associated with elevated L1/L2 CpG methylation levels in HIV-positive women.

IMPACT:

HPV DNA CpG methylation is a promising triage option in HIV-positive women testing positive for HR-HPV types and provides risk attribution in women with multiple HPV type infections.

PMID:
30237251
PMCID:
PMC6279505
[Available on 2019-12-01]
DOI:
10.1158/1055-9965.EPI-17-1051

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