title: Performance of a new HPV and biomarker assay in the management of hrHPV positive women: Subanalysis of the ongoing multicenter TRACE clinical trial (n > 6,000) to evaluate POU4F3 methylation as a potential biomarker of cervical precancer and cancer.
abstract: The ongoing Triage and Risk Assessment of Cervical Precancer by Epigenetic Biomarker (TRACE) prospective, multicenter study aimed to provide a clinical evaluation of the CONFIDENCE™ assay, which comprises a human papillomavirus (HPV) DNA and a human epigenetic biomarker test. Between 2013 and 2015 over 6,000 women aged 18 or older were recruited in Hungary. Liquid-based cytology (LBC), high-risk HPV (hrHPV) DNA detection and single target host gene methylation test of the promoter sequence of the POU4F3 gene by quantitative methylation-specific polymerase chain reaction (PCR) were performed from the same liquid-based cytology sample. The current analysis is focused on the baseline cross-sectional clinical results of 5,384 LBC samples collected from subjects aged 25 years or older. The performance of the CONFIDENCE HPV™ test was found to be comparable to the cobas® HPV test with good agreement. When applying the CONFIDENCE Marker™ test alone in hrHPV positives, it showed significantly higher sensitivity with matching specificity compared to LBC-based triage. For CIN3+ histological endpoint in the age group of 25-65 and 30-65, the methylation test of POU4F3 achieved relative sensitivities of 1.74 (95% CI: 1.25-2.33) and 1.64 (95% CI: 1.08-2.27), respectively, after verification bias adjustment. On the basis of our findings, POU4F3 methylation as a triage test of hrHPV positives appears to be a noteworthy method. We can reasonably assume that its quantitative nature offers the potential for a more objective and discriminative risk assessment tool in the prevention and diagnostics of high-grade cervical intraepithelial neoplasia (CIN) lesions and cervical cancer.
authors.affiliation: NEUMANN Diagnostics Ltd., Budapest, Hungary.|Cellcall Ltd., Budapest, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kocsis
authors.affiliation: NEUMANN Diagnostics Ltd., Budapest, Hungary.|Cellcall Ltd., Budapest, Hungary.|SYNLAB Hungary Ltd., GenoID Molecular Diagnostic Laboratory, Budapest, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Takács
authors.affiliation: Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Jeney
authors.affiliation: Second Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Schaff
authors.affiliation: Department of Obstetrics and Gynaecology, St. Stephan Hospital, Budapest, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Koiss
authors.affiliation: Second Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Járay
authors.affiliation: Second Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Sobel
authors.affiliation: Jósa András Regional Central Hospital, Nyíregyháza, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Pap
authors.affiliation: Department of Obstetrics and Gynaecology, St. Stephan Hospital, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Székely
authors.affiliation: Óbuda University, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Ferenci
authors.affiliation: Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Lai
authors.affiliation: NEUMANN Diagnostics Ltd., Budapest, Hungary.|Cellcall Ltd., Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Nyíri
authors.affiliation: NEUMANN Diagnostics Ltd., Budapest, Hungary.|Cellcall Ltd., Budapest, Hungary.|SYNLAB Hungary Ltd., GenoID Molecular Diagnostic Laboratory, Budapest, Hungary.
authors.forename: Márta
authors.initials: M
authors.lastname: Benczik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000821:virology; D019175:DNA Methylation; D015344:DNA Probes, HPV; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D018398:Homeodomain Proteins / Q000032:analysis* / Q000235:genetics; D006801:Humans; D006814:Hungary / Q000453:epidemiology; D008875:Middle Aged; D027383:Papillomaviridae / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000821:virology; D011230:Precancerous Conditions / Q000378:metabolism* / Q000821:virology; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D050821:Transcription Factor Brn-3C / Q000032:analysis* / Q000235:genetics; D014218:Triage; D002578:Uterine Cervical Dysplasia / Q000378:metabolism* / Q000821:virology / Q000737:chemistry; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000821:virology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D015344:DNA Probes, HPV; D004279:DNA, Viral; D018398:Homeodomain Proteins; C111223:POU4F3 protein, human; D050821:Transcription Factor Brn-3C
keywords: POU4F3 biomarker; cervical cancer; epigenetics; high-risk HPV; host gene methylation