Distinct human papillomavirus type 16 methylomes in cervical cells at different stages of premalignancy.
Distinct human papillomavirus type 16 methylomes in cervical cells at different stages of premalignancy.
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DOI：
10.1016/j.virol.2009.03.029
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发表时间：
2009-06-20
期刊：
影响因子：
3.7
通讯作者：
Neapolitano, Matthew
中科院分区：
文献类型：
--
作者：
Brandsma, Janet L.;Sun, Ying;Lizardi, Paul M.;Tuck, David P.;Zelterman, Daniel;Haines, G. Kenneth, III;Martel, Maritza;Harigopal, Malini;Schofield, Kevin;Neapolitano, Matthew
关键词：
人乳头瘤病毒（HPV）基因表达在宫颈癌发生过程中发生显著改变。由于失调基因经常表现出异常的DNA甲基化模式，我们假设在不同进展阶段的宫颈样本中对HPV甲基化组进行全面定位将揭示具有临床意义的模式。为了验证这一假设，从接受常规宫颈癌筛查的妇女中获得了13个hpv16阳性样本。通过亚硫酸盐测序，所有样品中98.7%的HPV16 CpGs获得了完整的甲基化数据。大多数HPV16 CpGs未甲基化或仅在一个样本中甲基化。其他CpGs的甲基化水平从每个样本的HPV16拷贝的11%到100%不等。结果显示出三种主要模式和一种模式的两种变体。这些模式显示了很少或没有甲基化(A)， E1和E6基因的低水平甲基化(B)，以及E5/L2/L1区域的许多CpGs的高水平甲基化(C)。通常，A型与阴性细胞学相关，B型与低级别病变相关，C型与高级别病变相关。然后根据HPV16 DNA甲基化模式和独立的病理诊断对宫颈病变的严重程度进行排名。两种评定方法的统计分析结果具有高度显著的一致性。总之，对宫颈细胞临床样本中的HPV16 DNA甲基化组的分析导致了不同甲基化模式的鉴定，经过更大规模的研究验证，这些甲基化模式可能作为肿瘤宫颈进展的生物标志物具有潜在的效用。
Human papillomavirus (HPV) gene expression is dramatically altered during cervical carcinogenesis. Because dysregulated genes frequently show abnormal patterns of DNA methylation, we hypothesized that comprehensive mapping of the HPV methylomes in cervical samples at different stages of progression would reveal patterns of clinical significance. To test this hypothesis, thirteen HPV16-positive samples were obtained from women undergoing routine cervical cancer screening. Complete methylation data were obtained for 98.7% of the HPV16 CpGs in all samples by bisulfite-sequencing. Most HPV16 CpGs were unmethylated or methylated in only one sample. The other CpGs were methylated at levels ranging from 11% to 100% of the HPV16 copies per sample. The results showed three major patterns and two variants of one pattern. The patterns showed minimal or no methylation (A), low level methylation in the E1 and E6 genes (B), and high level methylation at many CpGs in the E5/L2/L1 region (C). Generally, pattern A was associated with negative cytology, pattern B with low-grade lesions, and pattern C with high-grade lesions. The severity of the cervical lesions was then ranked by the HPV16 DNA methylation patterns and, independently, by the pathologic diagnoses. Statistical analysis of the two rating methods showed highly significant agreement. In conclusion, analysis of the HPV16 DNA methylomes in clinical samples of cervical cells led to the identification of distinct methylation patterns which, after validation in larger studies, could have potential utility as biomarkers of neoplastic cervical progression.
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