Methylation markers FAM19A4 and miR124‐2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study

Abstract

In human papillomavirus (HPV) cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID-SCREEN is a EU-multicenter, retrospective study conducted to evaluate the clinical performance of the FAM19A4/ miR124-2 methylation-based molecular triage test as a substitute or addition to cytology as reflex testing of HPV screen positive women. FAM19A4/miR124-2 methylation test (QIAsure Methylation Test) was evaluated in 2384 HPV-positive cervical screening samples, from women 29-76 years of age, derived from four EU countries. Specimens were collected in ThinPrep or SurePath media, HPV-status, concurrent cytology, and histology diagnosis were provided by the parent institutes. The control population consisted of women with no evidence of disease within 2 years of follow-up. A total of 899 histologies were retrieved; 527 showed no disease, 124 CIN2 (5.2%), 228 CIN3 (9.6%) and 20 cervical cancers (0.8%); 19 of 20 screen-detected cervical cancers were found methylation-positive (sensitivity 95%). Overall specificity of FAM19A4/miR124-2 methylation test was 78.3% (n = 2013; 95%CI: 76-80). The negative predictive value of hrHPV positive, methylation-negative outcomes were 99.9% for cervical cancer (N = 1694; 95%CI: 99.6-99.99), 96.9% for ≥CIN3 (95%CI: 96-98), and 93.0% for ≥CIN2 (95%CI: 92-94).

Self-collected versus clinician-collected cervical samples for the detection of HPV infections by 14-type DNA and 7-type mRNA tests

“…It is known that molecular biomarkers are of vital importance in relation to the triage of patients in cervical screening programmes [ 28 ]. All current screening programs that utilize HPV-testing rely on cytology for triaging positive samples prior to referral for colposcopy.…”

Epigenetic Regulation of microRNAs in Cancer: Shortening the Distance from Bench to Bedside

“…Subsequently, several studies have validated the use of a methylation-based signature composed of a combination of miR-124 and other genes (MAL/miR-124-2, FAM19A4/miR-124-2...) as a triage test for the identification of premalignant lesions (cervical intraepithelial neoplasia) in high-risk human papillomavirus-positive women [ 120 , 121 ]. Furthermore, FAM19A4/miR-124-2 methylation analysis in large cohorts of patients confirmed its value as a high-sensitivity screening method for the diagnosis of cervical cancer [ 122 , 123 ].…”

Performance of DNA methylation‐based biomarkers in the cervical cancer screening program of northern Portugal: A feasibility study

“…This was likely due to the use of the same DNA sample extracted for hr HPV genotyping, which very rarely is deemed insufficient (0.44% in our experience8 ). We believe that this strategy reduces the rate of invalid tests since DNA extraction is used for both procedures, contrarily to QIAsure Methylation Test which requires a second extraction procedure 35. This probably accounts for the 10% rate of invalid tests disclosed in that multicenter…”