the role of fam19a4 and hsa-mir-124 methylation in predicting prognosis of untreated cervical intraepithelial neoplasia 2 (cin 2)

Conditions: Cervical Intraepithelial Neoplasia Grade 2; DNA Methylation

Summary: high-risk precancerous cervical lesions are divided into stage 2 and 3 cervical intraepithelial neoplasia (cin 2 and 3). cin 3 represents a direct pre-stage of invasive cancer, has a high rate of progression and a high degree of agreement with the final histological diagnosis. in cin 2 lesions, the rate of agreement with the final histological diagnosis is lower and the rate of spontaneous regression is higher. due to the higher rate of regression and possible complications after excisional treatment, conservative active monitoring can be considered in selected young cin 2 patients. a recent meta-analysis reported a high rate of spontaneous clinical regression of cin 2, particularly in women under 30 years old. there are currently no prospectively validated prognostic biomarkers to determine which cin 2 will progress to higher grade and which will regress to lower grade of change. recent research has studied hpv methylation and microbiome analysis as biomarkers. a number of studies have shown that host cell dna methylation levels in cervical scrapes increase with underlying cervical disease severity and are highest in cervical cancer. dna methylation involves the covalent binding of a methyl group to the 5´ position of a cytosine molecule in cpg dinucleotides. besides global hypomethylation, the overall loss of methylation during carcinogenesis, resulting in chromosomal instability, and the silencing of tumour suppressor genes by local hypermethylation of cpg-rich promoter regions contribute to cancer development. gene promoter methylation can be easily accessed by sensitive, quantitative methylation-specific pcr providing an objective test outcome. the aim of this study was to determine the effect of the methylation rate of two suppressor genes- fam19a4 and hsa-mir-124 on the rate of cin 2 regression, persistence or progression in women younger than 36 years (≤35 years old).


Eligibility criteria:
inclusion criteria: * histologically confirmed cin 2 (with biopsy of colposcopically suspicious changes in the cervix) * age under 30 years * satisfactory colposcopy (transformation zone fully visible) * size of change below 75% of transformation zone * the change in the ectocervix is fully visible * age 30-35 years, if the patient is non-smoker and the change in the cervix does not exceed 50% of the area of the transformation zone * signing an informed consent to participate in the survey * willingness to perform inspections every 6 months exclusion criteria: * age 36 years or older * unsatisfactory colposcopy (transformation zone not fully visible) * size of change exceeds 75% of the transformation zone * the change in the ectocervix is not completely visible * age 30-35 years for smokers or if the change exceeds 50% of the area of the transformation zone * suspicted glandular precancerous changes * histologically verified cin 2 with cytological changes of glandular cells * colposcopically suspected invasive disease * histologically verified cin 2 and histologically verified ais * histologically verified cin 2 and histologically verified invasive cancer elsewhere in the cervix * refusal to sign participation in the survey * unwillingness to perform control examinations * weakness of an immune system * cervical conization performed in the past * treatment with local immunomodulators

Keywords: cin 2 prognosis dna hypermethylation fam19a4 hsa-mir-124 tumor suppressor genes diagnostic implications