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

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.

• Authors: Ana Gradissimo, Jessica Lam, John D Attonito, Joel Palefsky, L Stewart Massad, Xianhong Xie, Isam-Eldin Eltoum, Lisa Rahangdale, Margaret A Fischl, Kathryn Anastos, Howard Minkoff, Xiaonan Xue, Gypsyamber D'Souza, Lisa C Flowers, Christine Colie, Sadeep Shrestha, Nancy A Hessol, Howard D Strickler, Robert D Burk
• Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 27 Issue 12 Pg. 1407-1415 (12 2018) ISSN: 1538-7755 [Electronic] United States
• PMID: 30237251 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2018 American Association for Cancer Research.

Topics

• Adult
• Case-Control Studies
• Female
• Genomics (methods)
• HIV Infections (complications, pathology)
• Humans
• Methylation
• Papillomavirus Infections (virology)
• Risk Factors