title: FAM19A4 methylation analysis in self-samples compared with cervical scrapes for detecting cervical (pre)cancer in HPV-positive women.
abstract: BACKGROUND
  High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (⩾CIN3 (cervical intraepithelial neoplasia grade 3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking.
  
  
  METHODS
  We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for ⩾CIN3 detection in hrHPV-positive women (n=450,18-66 years).
  
  
  RESULTS
  Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with ⩾CIN3 (Spearman's ρ 0.697, P<0.001). The performance of FAM19A4 methylation analysis and/or HPV16/18 genotyping did not differ significantly between sample types. In women ⩾30 years, ⩾CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75-1.05). In women <30 years, ⩾CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55-1.21). In both groups, ⩾CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes.
  
  
  CONCLUSIONS
  FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for ⩾CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples.
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Roosmarijn
authors.initials: R
authors.lastname: Luttmer
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Lise M A
authors.initials: LM
authors.lastname: De Strooper
authors.affiliation: Department of Obstetrics and Gynaecology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Maaike G
authors.initials: MG
authors.lastname: Dijkstra
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Berkhof
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.affiliation: Department of Pathology, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: van Kemenade
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rozendaal
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus MC University Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Theo J M
authors.initials: TJ
authors.lastname: Helmerhorst
authors.affiliation: UMC Utrecht Cancer Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: René H M
authors.initials: RH
authors.lastname: Verheijen
authors.affiliation: Roosevelt Clinic, Rooseveltstraat 67, 2321 CT Leiden, The Netherlands.
authors.forename: W Abraham
authors.initials: WA
authors.lastname: Ter Harmsel
authors.affiliation: Department of Obstetrics and Gynaecology, Flevo Hospital, Hospitaalweg 1, 1315 RA Almere, The Netherlands.
authors.forename: W Marchien
authors.initials: WM
authors.lastname: van Baal
authors.affiliation: Department of Obstetrics and Gynaecology, Sint Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands.
authors.forename: Peppino G C M
authors.initials: PG
authors.lastname: Graziosi
authors.affiliation: DDL Diagnostic Laboratory, Visseringlaan 25, 2288 ER Rijswijk, The Netherlands.
authors.forename: Wim G V
authors.initials: WG
authors.lastname: Quint
authors.affiliation: Department of Obstetrics and Gynaecology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Spruijt
authors.affiliation: Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis West, Oosterpark 9, 1091 AC Amsterdam, The Netherlands.
authors.forename: Dorenda K E
authors.initials: DK
authors.lastname: van Dijken
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
mesh_terms: D052685:Alphapapillomavirus / Q000302:isolation & purification*; D001706:Biopsy; D016207:Cytokines / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D011230:Precancerous Conditions / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: D016207:Cytokines; C000607939:TAFA4 protein, human