Cancer Biology & Epigenetics Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Doctoral Program in Molecular Pathology and Genetics, School of Medicine & Biomedical Sciences (ICBAS-UP), Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
Clin Epigenetics. 2023 Aug 2;15(1):125. doi: 10.1186/s13148-023-01537-2.
Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited specificity, has become the gold standard frontline for screening programs. Thus, the importance of effective triage strategies, including DNA methylation markers, has been emphasized. Despite the potential reported in individual studies, methylation markers still require validation before being recommended for clinical practice. This systematic review and meta-analysis aimed to evaluate the performance of DNA methylation-based biomarkers for detecting high-grade intraepithelial lesions (HSIL) in hrHPV-positive women.
Hence, PubMed, Scopus, and Cochrane databases were searched for studies that assessed methylation in hrHPV-positive women in cervical scrapes. Histologically confirmed HSIL was used as endpoint and QUADAS-2 tool enabled assessment of study quality. A bivariate random-effect model was employed to pool the estimated sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values.
Twenty-three studies were included in this meta-analysis, from which cohort and referral population-based studies corresponded to nearly 65%. Most of the women analyzed were Dutch, and CADM1, FAM19A4, MAL, and miR124-2 were the most studied genes. Pooled sensitivity and specificity were 0.68 (CI 95% 0.63-0.72) and 0.75 (CI 95% 0.71-0.80) for cervical intraepithelial neoplasia (CIN) 2+ detection, respectively. For CIN3+ detection, pooled sensitivity and specificity were 0.78 (CI 95% 0.74-0.82) and 0.74 (CI 95% 0.69-0.78), respectively. For pooled prevalence, PPV for CIN2+ and CIN3+ detection were 0.514 and 0.392, respectively. Furthermore, NPV for CIN2+ and CIN3+ detection were 0.857 and 0.938, respectively.
This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as triage tool for hrHPV-positive women in cervical cancer screening. Standardization and improved validation are, however, required. Nevertheless, these markers might represent an excellent alternative to cytology and genotyping for colposcopy referral of hrHPV-positive women, allowing for more cost-effective screening programs.
筛查在宫颈癌二级预防中起着关键作用。高风险人乳头瘤病毒（hrHPV）检测是一种高度敏感的检测方法，但特异性有限，已成为筛查计划的金标准一线方法。因此，包括 DNA 甲基化标记物在内的有效分流策略的重要性已经得到强调。尽管个别研究中报告了其潜在价值，但在推荐用于临床实践之前，甲基化标记物仍需要验证。本系统评价和荟萃分析旨在评估基于 DNA 甲基化的生物标志物在检测 hrHPV 阳性妇女中高级别上皮内病变（HSIL）中的性能。
因此，检索了 PubMed、Scopus 和 Cochrane 数据库中评估宫颈刮片中 hrHPV 阳性妇女甲基化的研究。以组织学证实的 HSIL 为终点，并使用 QUADAS-2 工具评估研究质量。采用双变量随机效应模型对估计的敏感性和特异性以及阳性（PPV）和阴性（NPV）预测值进行汇总。
这项荟萃分析共纳入了 23 项研究，其中队列研究和转诊人群研究占近 65%。分析的大多数女性来自荷兰，CADM1、FAM19A4、MAL 和 miR124-2 是研究最多的基因。用于检测 CIN2+的汇总敏感性和特异性分别为 0.68（95%CI 0.63-0.72）和 0.75（95%CI 0.71-0.80），用于检测 CIN3+的汇总敏感性和特异性分别为 0.78（95%CI 0.74-0.82）和 0.74（95%CI 0.69-0.78）。对于汇总患病率，CIN2+和 CIN3+检测的 PPV 分别为 0.514 和 0.392。此外，CIN2+和 CIN3+检测的 NPV 分别为 0.857 和 0.938。
这项荟萃分析证实了基于 DNA 甲基化的生物标志物作为宫颈癌筛查中 hrHPV 阳性妇女分流工具的巨大潜力。然而，需要标准化和改进验证。尽管如此，这些标志物可能是对 hrHPV 阳性妇女行阴道镜检查时细胞学和基因分型的极好替代方法，能够实现更具成本效益的筛查计划。
