Advances in the Application of DNA Methylation in Cervical Lesions

doi:10.12280/gjfckx.20251049

Abstract

Abstract:

Cervical cancer is a common gynecological malignancy that seriously threatens women's health, and its occurrence and development is closely related to persistent infection with high risk human papilloma virus (HR-HPV). Current cervical cancer screening primarily relies on cytological examination and HR-HPV DNA testing. However, the former is subjective and has limited sensitivity, while the latter lacks specificity and may lead to overdiagnosis and overtreatment. DNA methylation, as a crucial epigenetic modification, is involved in the regulation of gene transcription. Recent studies have shown that HR-HPV infection can induce abnormal methylation at specific gene loci in host cells, and these alterations are closely associated with the progression of cervical intraepithelial neoplasia and the occurrence and development of cervical cancer. Detecting the methylation status of these specific genes demonstrates significant potential in triaging cervical cancer screening, prognostic evaluation, and monitoring therapeutic efficacy. This article reviews the application value of DNA methylation in cervical lesions, aiming to provide new insights for the precise prevention and treatment of cervical cancer.

Key words: DNA methylation, Uterine cervical neoplasms, Carcinoma, Cervical intraepithelial neoplasia, Papillomavirus infections, Early diagnosis, Therapy, Prognosis

ZHANG Yan, SONG Shu-fang. Advances in the Application of DNA Methylation in Cervical Lesions[J]. Journal of International Obstetrics and Gynecology, 2026, 53(2): 206-210.

Figures/Tables 2

References 28

[1]	Xu M, Cao C, Wu P, et al. Advances in cervical cancer: current insights and future directions[J]. Cancer Commun(Lond), 2025, 45(2):77-109. doi: 10.1002/cac2.12629.
[2]	Liu Y, Ai H. Comprehensive insights into human papillomavirus and cervical cancer: Pathophysiology, screening, and vaccination strategies[J]. Biochim Biophys Acta Rev Cancer, 2024, 1879(6): 189192. doi: 10.1016/j.bbcan.2024.189192.
[3]	Dick S, Heideman D, Berkhof J, et al. Clinical indications for host-cell DNA methylation markers in cervical screening and management of cervical intraepithelial neoplasia: A review[J]. Tumour Virus Res, 2025, 19:200308. doi: 10.1016/j.tvr.2024.200308.
[4]	Salta S, Lobo J, Magalhães B, et al. DNA methylation as a triage marker for colposcopy referral in HPV-based cervical cancer screening: a systematic review and meta-analysis[J]. Clin Epigenetics, 2023, 15(1):125. doi: 10.1186/s13148-023-01537-2. pmid: 37533074
[5]	Pavelescu LA, Mititelu-Zafiu NL, Mindru DE, et al. Molecular Insights into HPV-Driven Cervical Cancer: Oncoproteins, Immune Evasion, and Epigenetic Modifications[J]. Microorganisms, 2025, 13(5):1000. doi: 10.3390/microorganisms13051000.
[6]	Liu H, Ma H, Li Y, et al. Advances in epigenetic modifications and cervical cancer research[J]. Biochim Biophys Acta Rev Cancer, 2023, 1878(3): 188894. doi: 10.1016/j.bbcan.2023.188894.
[7]	Yadav C, Yadav R, Chabbra R, et al. Overview of genetic and epigenetic regulation of human papillomavirus and apoptosis in cervical cancer[J]. Apoptosis, 2023, 28(5/6):683-701. doi: 10.1007/s10495-023-01812-w.
[8]	Peng S, Zhang X, Wu Y. Potential applications of DNA methylation testing technology in female tumors and screening methods[J]. Biochim Biophys Acta Rev Cancer, 2023, 1878(5): 188941. doi: 10.1016/j.bbcan.2023.188941.
[9]	Alhudhud M, Maqsood S, Hussein ME, et al. Cervical cancer screening: a comparative study of TruScreen vs. Pap Smear[J]. BMC Womens Health, 2025, 25(1):198. doi: 10.1186/s12905-025-03733-z.
[10]	Sørbye S, Falang BM, Antonsen M, et al. Genotype-Specific HPV mRNA Triage Improves CIN2+ Detection Efficiency Compared to Cytology: A Population-Based Study of HPV DNA-Positive Women[J]. Pathogens, 2025, 14(8):749. doi: 10.3390/pathogens14080749.
[11]	Vallely A, Saville M, Badman SG, et al. Point-of-care HPV DNA testing of self-collected specimens and same-day thermal ablation for the early detection and treatment of cervical pre-cancer in women in Papua New Guinea: a prospective, single-arm intervention trial (HPV-STAT)[J]. Lancet Glob Health, 2022, 10(9):e1336-e1346. doi: 10.1016/S2214-109X(22)00271-6. pmid: 35878625
[12]	Mathews CS, Sargent A, Cuschieri K, et al. HPValidate-human papillomavirus testing with DNA and mRNA assays on self-collected samples in cervical screening: comparison of test characteristics on three self-sampling devices[J]. Br J Cancer, 2025, 133(5):665-673. doi: 10.1038/s41416-025-03102-5.
[13]	Xue P, Dang L, Kong LH, et al. Deep learning enabled liquid-based cytology model for cervical precancer and cancer detection[J]. Nat Commun, 2025, 16(1):3506. doi: 10.1038/s41467-025-58883-3.
[14]	Loopik DL, Koenjer LM, Siebers AG, et al. Benefit and burden in the Dutch cytology-based vs high-risk human papillomavirus-based cervical cancer screening program[J]. Am J Obstet Gynecol, 2021, 224(2):200.e1-200.e9. doi: 10.1016/j.ajog.2020.08.026.
[15]	Ramírez AT, Mesher D, Baena A, et al. Impact of knowledge of human papillomavirus positivity on cervical cytology performance in Latin America[J]. J Natl Cancer Inst, 2025, 117(4):644-652. doi: 10.1093/jnci/djae283.
[16]	Das S, Wentzensen N, Sawaya GF, et al. Primary human papillomavirus testing vs cotesting: clinical outcomes in populations with different disease prevalence[J]. J Natl Cancer Inst, 2024, 116(9):1525-1529. doi: 10.1093/jnci/djae117.
[17]	Zhang W, Zhao J, Fan X, et al. Targeted demethylation of the EphA7 promoter inhibits tumorigenesis via the SP1/DNMT1 and PI3K/AKT axes and improves the response to multiple therapies in cervical cancer[J]. Cell Death Dis, 2025, 16(1):324. doi: 10.1038/s41419-025-07512-4.
[18]	Cheng X, Chai R, Zhang T, et al. A novel methylation-detection panel for HPV associated high-grade squamous intraepithelial lesion and cervical cancer screening[J]. Sci Rep, 2024, 14(1):25556. doi: 10.1038/s41598-024-75047-3. pmid: 39462105
[19]	Loaeza-Loaeza J, Illades-Aguiar B, Del Moral-Hernández O, et al. The CpG island methylator phenotype increases the risk of high-grade squamous intraepithelial lesions and cervical cancer[J]. Clin Epigenetics, 2022, 14(1):4. doi: 10.1186/s13148-021-01224-0. pmid: 34991696
[20]	Lu Y, Wu H, Fu K, et al. PAX1 methylation as a robust predictor: developing and validating a nomogram for assessing endocervical curettage (ECC) necessity in human papillomavirus16/18-positive women undergoing colposcopy[J]. Clin Epigenetics, 2024, 16(1):77. doi: 10.1186/s13148-024-01691-1. pmid: 38849868
[21]	Li N, He Y, Mi P, et al. ZNF582 methylation as a potential biomarker to predict cervical intraepithelial neoplasia type Ⅲ/worse: A meta-analysis of related studies in Chinese population[J]. Medicine(Baltimore), 2019, 98(6):e14297. doi: 10.1097/MD.0000000000014297.
[22]	Vink FJ, Meijer C, Hesselink AT, et al. FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years[J]. Clin Infect Dis, 2023, 76(3):e827-e834. doi: 10.1093/cid/ciac433.
[23]	Kremer WW, Dick S, Heideman D, et al. Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study)[J]. J Clin Oncol, 2022, 40(26):3037-3046. doi: 10.1200/JCO.21.02433.
[24]	Pruski D, Millert-Kalińska S, Lis A, et al. Evaluation of the Use of Methylation as a New Tool for the Diagnostics and Progression of Squamous Intraepithelial Lesions[J]. Int J Mol Sci, 2024, 25(22):11863. doi: 10.3390/ijms252211863.
[25]	Al Roomy M, Chehadeh W, Al Awadhi R. Prediction of cervical cancer precursor lesions by quantitative methylation specific PCR: A retrospective study[J]. Cytopathology, 2023, 34(3):204-210. doi: 10.1111/cyt.13213.
[26]	Yang Y, Wen X, Wang L. Advancements in DNA methylation technologies and their application in cancer diagnosis[J]. Epigenetics, 2025, 20(1):2539995. doi: 10.1080/15592294.2025.2539995.
[27]	Bautista J, Lopez-Cortes A. Oncogenic viruses rewire the epigenome in human cancer[J]. Front Cell Infect Microbiol, 2025, 15:1617198. doi: 10.3389/fcimb.2025.1617198.
[28]	Gilham C, Nedjai B, Scibior-Bentkowska D, et al. Long-term prediction by DNA methylation of high-grade cervical intraepithelial neoplasia: Results of the ARTISTIC cohort[J]. Int J Cancer, 2024, 155(1):81-92. doi: 10.1002/ijc.34913.

标志物	主要临床用途	敏感度	特异度	优势	局限性
PAX1^[20]	HPV阳性分流，预测ECC必要性	中	高	特异度高，尤其在HPV16/18阳性人群中预测价值高	敏感度相对较低；可能存在人群差异
ZNF582^[21]	HPV阳性分流	中-高	高	在亚洲人群中性能稳定	在其他人群中的普适性需进一步验证
FAM19A4/miR124-2^{[4,22 -23]}	HPV阳性分流；预后预测（病变消退）	中-高	中-高	大型前瞻性研究支持；高阴性预测值；具有预后预测价值	对宫颈腺癌的检测效能待评估
CADM1/EPB41L3^[18]	HPV阳性分流，常组合使用	中-高	中-高	组合使用可提升整体性能	单一标志物性能可能有限
多基因Panel（如S5）^[24]	长期风险预测	高	中	评估甲基化负荷，预测远期进展风险	检测成本与分析复杂性相对较高

标志物	主要临床用途	敏感度	特异度	优势	局限性
PAX1^[20]	HPV阳性分流，预测ECC必要性	中	高	特异度高，尤其在HPV16/18阳性人群中预测价值高	敏感度相对较低；可能存在人群差异
ZNF582^[21]	HPV阳性分流	中-高	高	在亚洲人群中性能稳定	在其他人群中的普适性需进一步验证
FAM19A4/miR124-2^{[4,22 -23]}	HPV阳性分流；预后预测（病变消退）	中-高	中-高	大型前瞻性研究支持；高阴性预测值；具有预后预测价值	对宫颈腺癌的检测效能待评估
CADM1/EPB41L3^[18]	HPV阳性分流，常组合使用	中-高	中-高	组合使用可提升整体性能	单一标志物性能可能有限
多基因Panel（如S5）^[24]	长期风险预测	高	中	评估甲基化负荷，预测远期进展风险	检测成本与分析复杂性相对较高