Absence of FAM19A4/miR124-2 DNA Methylation and Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia

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In the Dutch CONCERVE study reported in the Journal of Clinical Oncology, Kremer et al found that the absence of FAM19A4/miR124-2 DNA methylation was associated with a high rate of clinical regression of high-grade cervical intraepithelial neoplasia over 24 months among women treated with a “wait-and-see” approach rather than surgery.

As stated by the investigators, “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.”

Study Details

The study included 114 women—80 with CIN2 and 34 with CIN3—enrolled at three clinics in the Netherlands between May 2017 and January 2018 and followed in a “wait-and-see” policy for 24 months. FAM19A4/miR124-2 methylation was evaluated in clinician-collected baseline samples. Every 6 months, human papillomavirus (HPV) testing and cytology were conducted and colposcopic examination was performed by a gynecologist to exclude disease progression.

Two biopsies were taken at the final study visit. Clinical regression was defined as histologically confirmed absence of CIN2+ or an HPV-negative sample with normal cytology.

Key Findings

Overall, 44 patients had positive FAM19A4/miR124-2 methylation tests, 49 had negative tests, and 2 had invalid tests at baseline.

During the study period, 65.8% of patients (75 of 114) did not receive surgical treatment. Surgery was performed in 39 due to clinical progression in 24, a persistent CIN2 or CIN3 lesion at the final study visit in 8, or at their own request in 7.

Overall, clinical regression occurred in 67 patients and clinical progression occurred in 25. The clinical regression rate was higher among patients with a negative FAM19A4/miR124-2 methylation test (74.7%, 95% confidence interval [CI] = 65.7%–81.7%) than among those with a positive methylation test (51.4%, 95% CI = 34.6%–65.9%, P = .013).

Clinical regression rates among patients with negative methylation tests were highest among patients with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASC-US/LSIL) and HPV-positive patients negative for HPV16. Among 59 patients with ASC-US/LSIL, regression rates were 88.4% (95% CI = 81.7%–92.7%) among those with negative methylation tests vs 61.8% (95% CI = 40.6%–77.3%) among those with positive methylation tests (P = .006). Among 103 patients who were HPV-positive at baseline, 54 were positive for and 49 were negative for HPV16. Among patients with negative methylation tests, clinical regression rates were 85.1% (95% CI =77.2%–90.4%) among HPV-positive patients who were HPV16-negative and 44.7% (95% CI = 20.8%–66.2%) in those who were HPV16-positive.

The investigators concluded, “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.”

Johannes Berkhof, PhD, of Amsterdam UMC, Vrije Universiteit Amsterdam, is the corresponding author for the Journal of Clinical Oncology article. 

Disclosure: The study was supported by The Netherlands Organisation for Health Research and Development (ZonMw) and European Union’s Horizon 2020 Research and Innovation Programme. For full disclosures of the study authors, visit

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