Chinese Journal of Obstetrics and Gynecology | Research progress on methylation detection for cervical cancer screening and prognosis management

Methylation events are involved in the occurrence and development of cervical cancer. Methylation detection schemes for host genes or HPV DNA have been recommended by several guidelines for cervical cancer screening.

Recently, Professor Li Lei and Professor Chen Xiaojing from the Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and the National Clinical Research Center for Gynecological and Obstetric Diseases published an article titled "Research Progress of Methylation in Cervical Cancer Screening and Prognosis Management" in the "Chinese Journal of Obstetrics and Gynecology". This article comprehensively organizes and reviews the progress or outcome prediction, prognosis prediction and efficacy evaluation of methylation detection in cervical precancerous lesions worldwide.

1. The value of methylation testing for cervical cancer screening

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Data from studies on methylation testing for triaging high-risk HPV-positive individuals suggest that methylation testing has the potential to be an alternative to cytology as a triage option for HPV-positive women. The positive predictive value and negative predictive value of the EPB41L3 and JAM3 gene methylation detection program in CIN Ⅱ and above lesions (CIN2+) are significantly higher than those of cytology (P=0.395). In addition, the detection effect of combining PAX1 and JAM3 gene methylation to detect cervical lesions CIN2+ is significantly better than that of cytology.

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Methylation testing alone for cervical cancer screening The screening efficiency of methylation testing may not be inferior to the current HPV testing or cytology. Studies have shown that regardless of HPV positive or not, the overall detection rate of methylation testing for cervical cancer is >98%, including cervical adenocarcinoma and other rare pathological types. The results of these studies on methylation testing for cervical cancer screening are better than or similar to traditional screening methods.

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Methylation detection combined with other schemes for cervical cancer screening Barrett et al. used a methylation detection method containing 5,000 tumor suppressor gene CpG sites, combined with HPV detection, and the overall sensitivity of predicting CINⅢ+ was 89.7%, and the sensitivity was increased to 92.7% in people aged ≥30 years.

At present, it is generally believed that compared with a single screening scheme, methylation combined with HPV16/18 detection can further improve the accuracy of screening and more efficiently identify cervical cancer at an early stage. PAX1/JAM3 gene methylation combined with HPV 16/18 detection can increase the diagnostic specificity of CIN3+ by 96.1%.

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Methylation testing is used to manage minor abnormal cytology results. Methylation testing can be used for HPV-positive women with cytology results of atypical squamous cells of undetermined signification (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) who have indications for colposcopy referral to reduce unnecessary invasive colposcopy evaluations.

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The efficacy of methylation detection of samples from different sources is well consistent with the self-sampling device and medically obtained cervical vaginal exfoliated cell samples. The effect of urine-based molecular analysis in screening cervical cancer is no less than that of cervical exfoliated cells. In addition, studies have also used cell-free DNA in plasma to detect methylation status to screen for cervical cancer.

2. The value of methylation detection for cervical cancer prognosis monitoring and follow-up

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The predictive value of methylation testing for the outcome of cervical precancerous lesions Methylation testing has a forward-looking predictive value for the outcome of cervical precancerous lesions. A cohort study closely observed and followed up 114 patients with untreated CIN II or III for 2 years. The results showed that the cumulative conversion rate of FAM19A4/miR124-2 methylation negative in cervical exfoliated cells within 2 years was 74.7%. %, significantly higher than those with methylation positive (51.4%), and the cumulative negative conversion rate can be increased to 85.1% and 88.4% in the stratification of HPV16 negative or cytological results of ASCUS and LSIL.

Another study found that for patients with CINⅡ/Ⅲ after circular electroresection or cold knife conization, the JAM3, SOX1, SLIT2, TERT, and C13ORF18 gene methylation detection program in cervical exfoliated cells can be used to predict recurrence after treatment. The AUC values were all >0.920, among which JAM3 gene methylation detection had the highest sensitivity and specificity, which were 94.8% and 93.7% respectively.

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The predictive value of methylation detection for the prognosis of cervical cancer Methylation detection can be used as a method to predict the prognosis of patients with cervical cancer. The AUC value of the methylation status of 5 genes (including CPXM1, TRERF1, ZNF681, SLC39A14, and CORO6 genes) in cervical tissue to predict the overall survival (OS) time of patients with early cervical cancer was 0.928.

Multiple abnormal DNA methylation of genes related to apoptosis signaling pathways is associated with drug resistance in cervical cancer treatment. Hypomethylation of the ZNF582 gene is associated with chemotherapy resistance in cervical cancer. Hypomethylation of the ZNF582 and PAX1 genes indicates that cervical cancer is not effective in radiotherapy, leading to poor prognosis of cervical cancer.

In summary, methylation is closely related to the occurrence, progression, outcome and prognosis of cervical lesions, providing a reliable epigenetic technology route for cervical cancer screening and prognosis management. Methylation detection methods provide safe, convenient and effective technical support for achieving these goals, and have also preliminarily demonstrated their value in clinical diagnosis and monitoring in special groups such as immunodeficiency and pregnancy, and have great application potential.

The Chinese Journal of Obstetrics and Gynecology was founded in 1953. It is an academic journal of obstetrics and gynecology supervised by the China Association for Science and Technology and sponsored by the Chinese Medical Association. It is the most influential professional journal in the field of obstetrics and gynecology in my country, with a core impact factor of 3.052. It is included in more than 30 important retrieval systems at home and abroad, including the National Library of Medicine's Medline, PubMed, Scopus, CSCD, and the Chinese Science Citation Database.

The journal targets obstetricians and gynecologists as its main readers, reporting leading scientific research results and clinical diagnosis and treatment experience in the field of obstetrics and gynecology, as well as basic theoretical research that has a guiding role in obstetrics and gynecology and is closely integrated with obstetrics and gynecology.

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