Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study)

J Clin Oncol. 2022 Sep 10;40(26):3037-3046. doi: 10.1200/JCO.21.02433. Epub 2022 May 5.


Purpose: Cervical screening can prevent cancer by detection and treatment of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3). Screening also results in considerable overtreatment because many CIN2/3 lesions show spontaneous regression when left untreated. In this multicenter longitudinal cohort study of women with untreated CIN2/3, the prognostic value of FAM19A4/miR124-2 methylation was evaluated for clinical regression.

Patients and methods: Women with CIN2/3 were prospectively followed for 24 months. Surgical excision was replaced by a wait-and-see policy. FAM19A4/miR124-2 methylation was evaluated on all clinician-collected samples and self-collected samples collected at baseline. Every 6 months, human papillomavirus (HPV) testing and cytology were conducted on a clinician-collected sample, and a colposcopic examination was performed by a gynecologist to exclude progression. At the final study visit, two biopsies were taken. Clinical regression was defined as histologically confirmed absence of CIN2+ or an HPV-negative clinician-collected sample with normal cytology. Regression incidences were estimated using the Kaplan-Meier method.

Results: One hundred fourteen women (median age, 30 years; range, 20-53 years) were included, 80 of whom were diagnosed with CIN2 and 34 with CIN3. During the study, 65.8% of women (75/114) did not receive surgical treatment. Women with a negative FAM19A4/miR124-2 result on the baseline clinician-collected sample showed more clinical regression (74.7%) than women with a positive methylation result (51.4%, P = .013). Regression in women with a negative FAM19A4/miR124-2 methylation test was highest when cytology was atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (88.4%) or HPV16 was negative (85.1%).

Conclusion: Most women with untreated CIN2/3 and a negative baseline FAM19A4/miR124-2 methylation test showed clinical regression. Methylation, in combination with cytology or HPV genotyping, can be used to support a wait-and-see policy in women with CIN2/3.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cytokines* / genetics
  • DNA Methylation
  • Early Detection of Cancer
  • Female
  • Genotype
  • Humans
  • Longitudinal Studies
  • MicroRNAs* / genetics
  • Middle Aged
  • Papillomaviridae
  • Papillomavirus Infections* / complications
  • Papillomavirus Infections* / genetics
  • Uterine Cervical Dysplasia* / genetics
  • Uterine Cervical Dysplasia* / pathology
  • Uterine Cervical Dysplasia* / surgery
  • Uterine Cervical Neoplasms* / diagnosis
  • Uterine Cervical Neoplasms* / genetics
  • Uterine Cervical Neoplasms* / surgery
  • Young Adult


  • Cytokines
  • MIRN124 microRNA, human
  • MicroRNAs
  • TAFA4 protein, human