DNA methylation at individual CpG-sites of EPB41L3, HTERT and FAM19A4 are useful for detection of cervical high-grade squamous intraepithelial lesions (HSIL) or worse: Analysis of individual CpG-sites outperforms averaging

IF 4.7 Q1 VIROLOGY Tumour Virus Research Pub Date : 2024-07-01 DOI:10.1016/j.tvr.2024.200288
Monica Molano , Dorothy A. Machalek , Samuel Phillips , Grace Tan , Suzanne M. Garland , David Hawkes , Prisha Balgovind , Reza Haqshenas , Steve G. Badman , John Bolnga , Josephine Gabuzzi , Zure Kombati , Gloria M. Munnull , Julia ML. Brotherton , Marion Saville , John M. Kaldor , Pamela J. Toliman , Andrew J. Vallely , Gerald L. Murray
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引用次数: 0

Abstract

Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea.

Methylation of EPB41L3 (1–6 CpG-sites), hTERT (1–10 CpG-sites) and FAM19A4 (1–5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for FAM19A4 directed to the first exon region not explored previously.

In clinician-collected samples, methylation at CpG-sites 4 and 5 of EPB41L3 were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of EPB41L3 sites 2/4 plus FAM19A4 site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity].

Methylation at CpG-site 5 of FAM19A4 was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of FAM19A4 for cancer (0.77). Combined, FAM19A4 site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%.

In conclusion, methylation at individual CpG-sites of EPB41L3 and FAM19A4 outperformed global analysis and improved HSIL+ detection, warranting further investigation.

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EPB41L3、HTERT和FAM19A4的单个CpG位点的DNA甲基化有助于检测宫颈高级别鳞状上皮内病变(HSIL)或更严重的病变:对单个 CpG 位点的分析优于平均分析。
基因启动子的全局甲基化分析有望用于检测高危人类乳头瘤病毒(hrHPV)阳性妇女的高级别或更严重的鳞状上皮内病变(HSIL+)。然而,单个 CpG 位点甲基化数据的诊断性能有限。我们对巴布亚新几内亚自采样本和临床医生采集样本中预测 HSIL+ 的甲基化情况进行了研究。通过对 44 份 HPV+样本(4 例癌症、19 例 HSIL、4 例低度鳞状上皮内病变 (LSIL)、17 例正常样本)进行热测序,评估了 EPB41L3(1-6 个 CpG 位点)、hTERT(1-10 个 CpG 位点)和 FAM19A4(1-5 个 CpG 位点)的甲基化情况。针对 FAM19A4 设计了新的引物,引物指向以前未探究过的第一个外显子区域。在临床医生采集的样本中,EPB41L3的CpG位点4和5的甲基化是预测HSIL的最佳指标(AUC>0.83),CpG位点4是预测癌症的最佳指标(0.925)。EPB41L3 2/4位点和FAM19A4 1位点的组合是最佳的HSIL+标记物[敏感性100%,特异性63.2%]。在自采样本中,FAM19A4 的 CpG 位点 5 的甲基化是预测 HSIL 的最佳指标(0.67),而 FAM19A4 的 CpG 位点 1 和 3 则是预测癌症的最佳指标(0.77)。结合 FAM19A4 位点 1 和 HPV 16/18 检测,灵敏度为 82.6%,特异性为 61.9%。总之,EPB41L3 和 FAM19A4 单个 CpG 位点的甲基化优于全局分析,提高了 HSIL+ 的检测率,值得进一步研究。
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来源期刊
Tumour Virus Research
Tumour Virus Research Medicine-Infectious Diseases
CiteScore
6.50
自引率
2.30%
发文量
16
审稿时长
56 days
期刊最新文献
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