Methylation of High-Risk Human Papillomavirus Genomes Are Associated with Cervical Precancer in HIV-Positive Women.
Methylation of High-Risk Human Papillomavirus Genomes Are Associated with Cervical Precancer in HIV-Positive Women.
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DOI：
10.1158/1055-9965.epi-17-1051
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发表时间：
2018-12
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影响因子：
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通讯作者：
Burk RD
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文献类型：
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作者：
Gradissimo A;Lam J;Attonito JD;Palefsky J;Massad LS;Xie X;Eltoum IE;Rahangdale L;Fischl MA;Anastos K;Minkoff H;Xue X;D'Souza G;Flowers LC;Colie C;Shrestha S;Hessol NA;Strickler HD;Burk RD
人类免疫缺陷病毒（HIV）阳性女性因高危型人乳头瘤病毒（HR - HPV）而患与人乳头瘤病毒相关的宫颈肿瘤的风险很高。在HIV阴性女性中，人乳头瘤病毒基因组的甲基化与宫颈上皮内瘤变3级（CIN3）有关，但对于HIV阳性女性是否如此尚不清楚。
我们在妇女机构间HIV研究（WIHS）队列中设计了一项病例对照研究，将HIV阳性的CIN3病例（N = 72）与未检测到CIN2 +的HIV阳性对照进行比较。分析单位和匹配依据是人乳头瘤病毒类型感染。感染≥2种高危型人乳头瘤病毒类型的病例（N = 23；32%）针对每种高危型人乳头瘤病毒类型都有一个单独的对照。我们开发并利用了针对12种不同高危型人乳头瘤病毒的新一代测序（NGS）甲基化检测方法，重点关注L1/L2区域的CpG位点。
基于三分位数水平的二分法（T3与T1和T2相比），在多种α - 9（HPV16/31/35/58）和α - 7人乳头瘤病毒（HPV18/39/45）类型中观察到个体CpG位点甲基化水平在病例对照之间存在显著差异。对同源CpG位点进行组合分析（例如，HPV16 - L1 - 5608/HPV31 - L1 - 5521/HPV35 - L2L1 - 5570；比值比[OR] = 7.28；95%置信区间：2.75 - 19.3），以及（例如，HPV18 - L1 - 7062/HPV45 - L1 - 7066，OR = 6.94；95%置信区间：1.23 - 39.3）在单独的病例对照比较中具有显著性。在感染多种高危型人乳头瘤病毒的病例中，我们检验并证实了一种假设，即一种高危型人乳头瘤病毒类型的甲基化程度会高于检测到的其他类型，这与单个高危型人乳头瘤病毒与病变存在因果关系是一致的。
在HIV阳性女性中，CIN3与L1/L2 CpG甲基化水平升高有关。
在高危型人乳头瘤病毒类型检测呈阳性的HIV阳性女性中，人乳头瘤病毒DNA的CpG甲基化是一种有前景的分流选择，并为感染多种人乳头瘤病毒类型的女性提供了风险归因。
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. We designed a case-control study within the 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. 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 versus T1 and T2). Analyses combining homologous CpG sites (e.g., HPV16-L1–5608/HPV31-L1–5521/HPV35-L2L1–5570; odds ratio [OR]=7.28; 95% 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. CIN3 is associated with elevated L1/L2 CpG methylation levels in HIV-positive women. 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.