TY - JOUR
T1 - FAM19A4/miR124-2 methylation analysis as a triage test for HPV-positive women
T2 - cross-sectional and longitudinal data from a Dutch screening cohort
AU - Vink, F J
AU - Lissenberg-Witte, B I
AU - Meijer, C J L M
AU - Berkhof, J
AU - van Kemenade, F J
AU - Siebers, A G
AU - Steenbergen, R D M
AU - Bleeker, M C G
AU - Heideman, D A M
N1 - Funding Information: This work was supported by the SME Instrument in the Horizon 2020 Work Program of the European Commission (grant agreement ID: 666800 , VALID-SCREEN). Potential conflicts of interest: (1) D.H., C.M. and R.S. are minority shareholders of Self-screen B.V., a spin-off company of VUmc. (2) Self-screen B.V. holds patents related to the work (i.e. high-risk HPV test and methylation markers for cervical screening) and has developed and manufactured the methylation assay, which is licensed to QIAGEN (QIAsure® Methylation Test). (3) D.H. has been on the speakers' bureau of QIAGEN and serves occasionally on the scientific advisory boards of Pfizer and Bristol-Myers Squibb. (4) C.M. has received speaker fees from GSK, QIAGEN, SPMSD/Merck and Roche diagnostics, and served occasionally on the scientific advisory board (expert meeting) of GSK, QIAGEN, SPMSD/Merck and Roche. (6) C.M. has a very small number of shares of QIAGEN and MDxHealth and holds minority stock in Self-Screen B.V. Until April 2016 he was minority shareholder of Diassay B.V. (7) C.M. is part-time director of Self-screen B.V. since September 2017. (8) J.B. reports personal fees from GlaxoSmithKline and Merck; and non-financial support from DDL; the fees from GlaxoSmithKline and Merck were collected by his employer. All other authors declare no conflicts of interest. Funding Information: This work was supported by the SME Instrument in the Horizon 2020 Work Program of the European Commission (grant agreement ID: 666800, VALID-SCREEN). Potential conflicts of interest: (1) D.H., C.M. and R.S. are minority shareholders of Self-screen B.V., a spin-off company of VUmc. (2) Self-screen B.V. holds patents related to the work (i.e. high-risk HPV test and methylation markers for cervical screening) and has developed and manufactured the methylation assay, which is licensed to QIAGEN (QIAsure? Methylation Test). (3) D.H. has been on the speakers' bureau of QIAGEN and serves occasionally on the scientific advisory boards of Pfizer and Bristol-Myers Squibb. (4) C.M. has received speaker fees from GSK, QIAGEN, SPMSD/Merck and Roche diagnostics, and served occasionally on the scientific advisory board (expert meeting) of GSK, QIAGEN, SPMSD/Merck and Roche. (6) C.M. has a very small number of shares of QIAGEN and MDxHealth and holds minority stock in Self-Screen B.V. Until April 2016 he was minority shareholder of Diassay B.V. (7) C.M. is part-time director of Self-screen B.V. since September 2017. (8) J.B. reports personal fees from GlaxoSmithKline and Merck; and non-financial support from DDL; the fees from GlaxoSmithKline and Merck were collected by his employer. All other authors declare no conflicts of interest. Publisher Copyright: © 2020 European Society of Clinical Microbiology and Infectious Diseases Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - OBJECTIVES: The aim was to evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening.METHODS: We conducted a post hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30-60 years (n = 979). Cross-sectional cervical intraepithelial neoplasia (CIN) 3+ sensitivity, specificity, positive predictive value and negative predictive value as well as cumulative CIN3+ or cervical cancer risks after 9 and 14 years were compared for three baseline triage strategies: (1) cytology, (2) FAM19A4/miR124-2 methylation analysis and (3) combined FAM19A4/miR124-2 methylation with cytology.RESULTS: CIN3+ sensitivity of FAM19A4/miR124-2 methylation analysis was similar to that of cytology (71.3% vs 76.0%, ratio 0.94, 95% CI 0.84 to 1.05), at a lower specificity (78.3% vs 87.0%, ratio 0.90, 95% CI 0.86 to 0.94). Combining FAM19A4/miR124-2 methylation analysis with cytology resulted in a CIN3+ sensitivity of 84.6% (95% CI 78.3 to 90.8) at a specificity of 69.6% (95% CI 66.5 to 72.7). Similar 9- and 14-year CIN3+ risks for baseline cytology-negative women and baseline FAM19A4/miR124-2 methylation-negative women were observed, with risk differences of -0.42% (95% CI -2.1 to 1.4) and -0.07% (95% CI -1.9 to 1.9), respectively. The 14-year cumulative cervical cancer incidence was significantly lower for methylation-negative women compared to cytology-negative women (risk difference 0.98%, 95% CI 0.26 to 2.0).DISCUSSION: FAM19A4/miR124-2 methylation analysis has a good triage performance on baseline screening samples, with a cross-sectional CIN3+ sensitivity and long-term triage-negative CIN3+ risk equalling cytology triage. Therefore, FAM19A4/miR124-2 methylation analysis appears to be a good and objective alternative to cytology in triage scenarios in HPV-based cervical screening.
AB - OBJECTIVES: The aim was to evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening.METHODS: We conducted a post hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30-60 years (n = 979). Cross-sectional cervical intraepithelial neoplasia (CIN) 3+ sensitivity, specificity, positive predictive value and negative predictive value as well as cumulative CIN3+ or cervical cancer risks after 9 and 14 years were compared for three baseline triage strategies: (1) cytology, (2) FAM19A4/miR124-2 methylation analysis and (3) combined FAM19A4/miR124-2 methylation with cytology.RESULTS: CIN3+ sensitivity of FAM19A4/miR124-2 methylation analysis was similar to that of cytology (71.3% vs 76.0%, ratio 0.94, 95% CI 0.84 to 1.05), at a lower specificity (78.3% vs 87.0%, ratio 0.90, 95% CI 0.86 to 0.94). Combining FAM19A4/miR124-2 methylation analysis with cytology resulted in a CIN3+ sensitivity of 84.6% (95% CI 78.3 to 90.8) at a specificity of 69.6% (95% CI 66.5 to 72.7). Similar 9- and 14-year CIN3+ risks for baseline cytology-negative women and baseline FAM19A4/miR124-2 methylation-negative women were observed, with risk differences of -0.42% (95% CI -2.1 to 1.4) and -0.07% (95% CI -1.9 to 1.9), respectively. The 14-year cumulative cervical cancer incidence was significantly lower for methylation-negative women compared to cytology-negative women (risk difference 0.98%, 95% CI 0.26 to 2.0).DISCUSSION: FAM19A4/miR124-2 methylation analysis has a good triage performance on baseline screening samples, with a cross-sectional CIN3+ sensitivity and long-term triage-negative CIN3+ risk equalling cytology triage. Therefore, FAM19A4/miR124-2 methylation analysis appears to be a good and objective alternative to cytology in triage scenarios in HPV-based cervical screening.
KW - Biomarker
KW - Cervical cancer screening
KW - Cervical intraepithelial neoplasia (CIN)
KW - DNA hypermethylation
KW - Human genome methylation
KW - Pre-cancer
UR - http://www.scopus.com/inward/record.url?scp=85083338059&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.cmi.2020.03.018
DO - https://doi.org/10.1016/j.cmi.2020.03.018
M3 - Article
C2 - 32222459
SN - 1469-0691
VL - 27
SP - 125.e1-125.e6
JO - Clinical Microbiological and Infection
JF - Clinical Microbiological and Infection
IS - 1
ER -