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

Abstract

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.

Evaluation of FAM19A4/miR124‐2 methylation performance in the management of CIN3 diagnosed pregnant women

“…For methylation‐positive women routine clinical care would not change (eg, in Germany return visit every 8‐10 weeks with Pap smear and colposcopy). These findings are in line with the fact that the FAM19A4/miR124‐2 methylation test has previously shown to detect cervical cancer and advanced CIN2/3 lesions with a high short‐term cancer progression risk 18,22,23 and that women with a CIN2 or CIN3 smear that tested negative for FAM19A4/miR124‐2 methylation had a much higher regression rate than women with a FAM19A4/miR124‐2 methylation positive testing CIN2/3 20 . Women with a FAM19A4/miR124‐2 methylation negative smear also displayed much lower 14 years risk for CIN3+ compared to women with a methylation‐positive CIN3 smear 26 .…”

Assessing the risk of cervical neoplasia in the post‐HPV vaccination era

“…This is further supported by the fact that methylation positivity of FAM19A4 and miR‐124‐2 in CIN2/3 lesions appears to be associated with increased p16 INK4A /Ki‐67 immunoscores and low HPV‐E4 expression 51,52 underscoring the high specificity of the FAM19A4/miR124‐2 methylation test for nonproductive, transforming CIN2/3 lesions 52 . In addition, in a prospective clinical cohort study, the absence of FAM19A4/miR124‐2 methylation was found associated with a high regression rate of CIN2/3 lesions 53 further corroborating the value of cellular methylation analysis as a biomarker that distinguishes advanced from early lesions based on the level of epigenetic host‐cell alterations. In reference to HPV vaccination, it was noted that the detection of CIN3+ by FAM19A4/miR124‐2 methylation is similar for lesions caused by HPV16/18 and those cause by other hrHPV types 54 …”

DNA Methylation Analysis to predict Regression of high-grade anal Intraepithelial Neoplasia in HIV+ men (MARINE): a cohort study protocol

“…[12][13][14][15][16][17][18] A methylation negative test demonstrated a significantly lower 14-year cervical cancer risk among HPV-positive women than a cytology negative test. 19 Likewise, for anal cancer prevention, a methylation marker panel containing markers ASCL1 and ZNF582 was recently shown and validated to detect anal cancer and AIN3 at high accuracy. 20 21 In HGAIN, a heterogeneous methylation pattern was observed with either low methylation levels, suggestive of HGAIN with a low progression risk towards cancer, versus high methylation levels, or 'cancer-like' methylation patterns, with a high risk of progression towards cancer.…”

“…DNA methylation markers, such as FAM19A4/miR124-2 methylation, have been thoroughly investigated and validated for application in cervical cancer screening 12–18. A methylation negative test demonstrated a significantly lower 14-year cervical cancer risk among HPV-positive women than a cytology negative test 19. Likewise, for anal cancer prevention, a methylation marker panel containing markers ASCL1 and ZNF582 was recently shown and validated to detect anal cancer and AIN3 at high accuracy 20 21.…”