Methylation of high-risk human papillomavirus genomes are associated with cervical precancer in HIV-positive women

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 (Nan) Xue, Gypsyamber D'Souza, Lisa C. Flowers, Christine Colie, Sadeep Shrestha, Nancy A. Hessol, Howard Strickler, Robert D. Burk

Research output: Contribution to journalArticle

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 HIVnegative 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 CIN2þ. The unit of analysis and matching was HPV-type infection. Cases with 2HR-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.

Original languageEnglish (US)
Pages (from-to)1407-1415
Number of pages9
JournalCancer Epidemiology Biomarkers and Prevention
Volume27
Issue number12
DOIs
StatePublished - Dec 1 2018

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Human Genome
Methylation
HIV
Cervical Intraepithelial Neoplasia
Confidence Intervals
Triage
DNA Methylation
Infection
Individuality
Cohort Studies
Genome

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Methylation of high-risk human papillomavirus genomes are associated with cervical precancer in HIV-positive women. / Gradissimo, Ana; Lam, Jessica; Attonito, John D.; Palefsky, Joel; Massad, L. Stewart; Xie, Xianhong; Eltoum, Isam Eldin; Rahangdale, Lisa; Fischl, Margaret A.; Anastos, Kathryn; Minkoff, Howard; Xue, Xiaonan (Nan); D'Souza, Gypsyamber; Flowers, Lisa C.; Colie, Christine; Shrestha, Sadeep; Hessol, Nancy A.; Strickler, Howard; Burk, Robert D.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 27, No. 12, 01.12.2018, p. 1407-1415.

Research output: Contribution to journalArticle

Gradissimo, A, Lam, J, Attonito, JD, Palefsky, J, Massad, LS, Xie, X, Eltoum, IE, Rahangdale, L, Fischl, MA, Anastos, K, Minkoff, H, Xue, XN, D'Souza, G, Flowers, LC, Colie, C, Shrestha, S, Hessol, NA, Strickler, H & Burk, RD 2018, 'Methylation of high-risk human papillomavirus genomes are associated with cervical precancer in HIV-positive women', Cancer Epidemiology Biomarkers and Prevention, vol. 27, no. 12, pp. 1407-1415. https://doi.org/10.1158/1055-9965.EPI-17-1051
Gradissimo, Ana ; Lam, Jessica ; Attonito, John D. ; Palefsky, Joel ; Massad, L. Stewart ; Xie, Xianhong ; Eltoum, Isam Eldin ; Rahangdale, Lisa ; Fischl, Margaret A. ; Anastos, Kathryn ; Minkoff, Howard ; Xue, Xiaonan (Nan) ; D'Souza, Gypsyamber ; Flowers, Lisa C. ; Colie, Christine ; Shrestha, Sadeep ; Hessol, Nancy A. ; Strickler, Howard ; Burk, Robert D. / Methylation of high-risk human papillomavirus genomes are associated with cervical precancer in HIV-positive women. In: Cancer Epidemiology Biomarkers and Prevention. 2018 ; Vol. 27, No. 12. pp. 1407-1415.
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T1 - Methylation of high-risk human papillomavirus genomes are associated with cervical precancer in HIV-positive women

AU - Gradissimo, Ana

AU - Lam, Jessica

AU - Attonito, John D.

AU - Palefsky, Joel

AU - Massad, L. Stewart

AU - Xie, Xianhong

AU - Eltoum, Isam Eldin

AU - Rahangdale, Lisa

AU - Fischl, Margaret A.

AU - Anastos, Kathryn

AU - Minkoff, Howard

AU - Xue, Xiaonan (Nan)

AU - D'Souza, Gypsyamber

AU - Flowers, Lisa C.

AU - Colie, Christine

AU - Shrestha, Sadeep

AU - Hessol, Nancy A.

AU - Strickler, Howard

AU - Burk, Robert D.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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 HIVnegative 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 CIN2þ. The unit of analysis and matching was HPV-type infection. Cases with 2HR-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.

AB - 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 HIVnegative 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 CIN2þ. The unit of analysis and matching was HPV-type infection. Cases with 2HR-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.

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