TY - JOUR
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
AU - D'Souza, Gypsyamber
AU - Flowers, Lisa C.
AU - Colie, Christine
AU - Shrestha, Sadeep
AU - Hessol, Nancy A.
AU - Strickler, Howard D.
AU - Burk, Robert D.
N1 - Funding Information:
The authors would like to acknowledge the contribution of the Epigenomics Core Facility at the Albert Einstein College of Medicine for providing assistance with the Illumina sequencing and helpful discussions on this work. HPV testing and the current analyses were supported by the NCI (grant numbers R01-CA-085178 and R01-CA-174634, to H.D. Strickler; P30-CA-013330). Data in this article were collected by the Women's Interagency HIV Study (WIHS). WIHS (principal investigators): UAB-MS WIHS (to M. Saag, M.C. Kempf, and D. Konkle-Parker), U01-AI-103401; Atlanta WIHS (to I. Ofotokun and G. Wingood), U01-AI-103408; Bronx WIHS (to K. Anastos), U01-AI-035004; Brooklyn WIHS (to H. Minkoff and D. Gustafson), U01-AI-031834; Chicago WIHS (to M. Cohen and A. French), U01-AI-034993; Metropolitan Washington WIHS (to S. Kassaye), U01-AI-034994; Miami WIHS (to M.A. Fischl and L. Metsch), U01-AI-103397; UNC WIHS (to A. Adimora), U01-AI-103390; Connie Wofsy Women's HIV Study, Northern California (to R. Greenblatt, B. Aouizerat, and P. Tien), U01-AI-034989; WIHS Data Management and Analysis Center (to S. Gange and E. Golub), U01-AI-042590; Southern California WIHS (to J. Milam), U01-HD-032632 (WIHS I – WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID; grant number P30-AI-050410, to R. Swanstrom), with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NCI, the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA).
Funding Information:
The authors would like to acknowledge the contribution of the Epigenomics Core Facility at the Albert Einstein College of Medicine for providing assistance with the Illumina sequencing and helpful discussions on this work. HPV testing and the current analyses were supported by the NCI (grant numbers R01-CA-085178 and R01-CA-174634, to H.D. Strickler; P30-CA-013330). Data in this article were collected by the Women's Interagency HIV Study (WIHS). WIHS (principal investigators): UAB-MS WIHS (to M. Saag, M.C. Kempf, and D. Konkle-Parker), U01-AI-103401; Atlanta WIHS (to I. Ofotokun and
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/12
Y1 - 2018/12
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.
UR - http://www.scopus.com/inward/record.url?scp=85057720480&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-17-1051
DO - 10.1158/1055-9965.EPI-17-1051
M3 - Article
C2 - 30237251
AN - SCOPUS:85057720480
VL - 27
SP - 1407
EP - 1415
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
SN - 1055-9965
IS - 12
ER -