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Int J Cancer. 2016 Feb 15;138(4):992-1002. doi: 10.1002/ijc.29824. Epub 2015 Sep 14.

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).

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Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Obstetrics and Gynecology, Flevo Hospital, Almere, The Netherlands.
Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Obstetrics and Gynecology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Department of Obstetrics and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Gynecology, Roosevelt Clinic, Leiden, The Netherlands.
Department of Obstetrics and Gynecology, Sint Antonius Hospital, Nieuwegein, The Netherlands.
DDL Diagnostic Laboratory, Rijswijk, The Netherlands.


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.


DNA methylation; cervical cancer; cervical intraepithelial neoplasia; cervical scrapes; human papillomavirus; qMSP

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