title: Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study).
abstract: Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥ CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥ CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥ CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥ CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥ 30 years (n = 287), ≥ CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8-68.4) compared to 47.6% (95%CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥ 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥ CIN3.
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Roosmarijn
authors: R
authors: Luttmer
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Lise M A
authors: LM
authors: De Strooper
authors: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Johannes
authors: J
authors: Berkhof
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Peter J F
authors: PJ
authors: Snijders
authors: Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Maaike G
authors: MG
authors: Dijkstra
authors: Department of Obstetrics and Gynecology, Flevo Hospital, Almere, The Netherlands.
authors: Margot H
authors: MH
authors: Uijterwaal
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Renske D M
authors: RD
authors: Steenbergen
authors: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Folkert J
authors: FJ
authors: van Kemenade
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Lawrence
authors: L
authors: Rozendaal
authors: Department of Obstetrics and Gynecology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors: Theo J M
authors: TJ
authors: Helmerhorst
authors: Department of Obstetrics and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Rene H M
authors: RH
authors: Verheijen
authors: Department of Gynecology, Roosevelt Clinic, Leiden, The Netherlands.
authors: W Abraham
authors: WA
authors: Ter Harmsel
authors: Department of Obstetrics and Gynecology, Flevo Hospital, Almere, The Netherlands.
authors: W Marchien
authors: WM
authors: Van Baal
authors: Department of Obstetrics and Gynecology, Sint Antonius Hospital, Nieuwegein, The Netherlands.
authors: Peppino G C M
authors: PG
authors: Graziosi
authors: DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
authors: Wim G V
authors: WG
authors: Quint
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Daniëlle A M
authors: DA
authors: Heideman
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Chris J L M
authors: CJ
authors: Meijer
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D018925:Chemokines / Q000235:genetics*; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005838:Genotype; D052162:Human papillomavirus 16 / Q000235:genetics*; D052161:Human papillomavirus 18 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D010045:Outpatients; D030361:Papillomavirus Infections / Q000150:complications; D012307:Risk Factors; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000821:virology; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000235:genetics / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; D018925:Chemokines; D016207:Cytokines; C000607939:TAFA4 protein, human
keywords: DNA methylation; cervical cancer; cervical intraepithelial neoplasia; cervical scrapes; human papillomavirus; qMSP