OBJECTIVES: Methylation marker analysis using bi-marker panel MAL/miR-124-2 is a promising triage test for identifying cervical (pre)cancer in high-risk human papillomavirus (hrHPV) positive women. Bi-marker panel MAL/miR-124-2 can be applied directly on self-sampled cervico-vaginal material and its sensitivity is non-inferior to that of cytology, yet at the cost of more colposcopy referrals. Our objective was to increase specificity of MAL/miR-124-2 methylation analysis by varying the assay thresholds and adding HPV16/18 genotyping. METHODS: 1019 hrHPV-positive women were selected from a randomized controlled self-sampling trial (PROHTECT-3; 33-63 years, n=46,001) and nine triage strategies with methylation testing of MAL/miR-124-2 and HPV16/18 genotyping were evaluated. The methylation assay threshold was set at four different predefined levels which correspond with clinical specificities for end-point cervical intra-epithelial grade 3 or worse (CIN3+) of 50%, 60%, 70%, and 80%. RESULTS: The CIN3+ sensitivity of methylation analysis decreased (73.5 to 44.9%) while specificity increased (47.2 to 83.4%) when increasing the assay threshold. CIN3+ sensitivity and specificity of HPV16/18 genotyping were 68.0% and 65.6%, respectively. Combined methylation analysis at threshold-80 and HPV16/18 genotyping yielded similar CIN3+ sensitivity as that of methylation only at threshold-50 (77.6%) with an increased specificity (54.8%). CONCLUSIONS: Combined triage by MAL/miR-124-2 methylation analysis with threshold-80 and HPV16/18 genotyping reaches high CIN3+ sensitivity with increased specificity to identify women with cervical (pre)cancer among HPV self-sample positive women. The combined strategy is attractive as it is fully molecular and identifies women at the highest risk of cervical (pre)cancer because of strongly elevated methylation levels and/or HPV16/18 positivity.
OBJECTIVES: Methylation marker analysis using bi-marker panel MAL/miR-124-2 is a promising triage test for identifying cervical (pre)cancer in high-risk human papillomavirus (hrHPV) positive women. Bi-marker panel MAL/miR-124-2 can be applied directly on self-sampled cervico-vaginal material and its sensitivity is non-inferior to that of cytology, yet at the cost of more colposcopy referrals. Our objective was to increase specificity of MAL/miR-124-2 methylation analysis by varying the assay thresholds and adding HPV16/18 genotyping. METHODS: 1019 hrHPV-positive women were selected from a randomized controlled self-sampling trial (PROHTECT-3; 33-63 years, n=46,001) and nine triage strategies with methylation testing of MAL/miR-124-2 and HPV16/18 genotyping were evaluated. The methylation assay threshold was set at four different predefined levels which correspond with clinical specificities for end-point cervical intra-epithelial grade 3 or worse (CIN3+) of 50%, 60%, 70%, and 80%. RESULTS: The CIN3+ sensitivity of methylation analysis decreased (73.5 to 44.9%) while specificity increased (47.2 to 83.4%) when increasing the assay threshold. CIN3+ sensitivity and specificity of HPV16/18 genotyping were 68.0% and 65.6%, respectively. Combined methylation analysis at threshold-80 and HPV16/18 genotyping yielded similar CIN3+ sensitivity as that of methylation only at threshold-50 (77.6%) with an increased specificity (54.8%). CONCLUSIONS: Combined triage by MAL/miR-124-2 methylation analysis with threshold-80 and HPV16/18 genotyping reaches high CIN3+ sensitivity with increased specificity to identify women with cervical (pre)cancer among HPV self-sample positive women. The combined strategy is attractive as it is fully molecular and identifies women at the highest risk of cervical (pre)cancer because of strongly elevated methylation levels and/or HPV16/18 positivity.
Authors: Megan A Clarke; Ana Gradissimo; Nicolas Wentzensen; Robert D Burk; Mark Schiffman; Jessica Lam; Christopher C Sollecito; Barbara Fetterman; Thomas Lorey; Nancy Poitras; Tina R Raine-Bennett; Philip E Castle Journal: Clin Cancer Res Date: 2018-02-02 Impact factor: 12.531
Authors: Wina Verlaat; Barbara C Snoek; Daniëlle A M Heideman; Saskia M Wilting; Peter J F Snijders; Putri W Novianti; Annina P van Splunter; Carel F W Peeters; Nienke E van Trommel; Leon F A G Massuger; Ruud L M Bekkers; Willem J G Melchers; Folkert J van Kemenade; Johannes Berkhof; Mark A van de Wiel; Chris J L M Meijer; Renske D M Steenbergen Journal: Clin Cancer Res Date: 2018-04-09 Impact factor: 12.531
Authors: Lise M A De Strooper; Viola M J Verhoef; Johannes Berkhof; Albertus T Hesselink; Helena M E de Bruin; Folkert J van Kemenade; Remko P Bosgraaf; Ruud L M Bekkers; Leon F A G Massuger; Willem J G Melchers; Renske D M Steenbergen; Peter J F Snijders; Chris J L M Meijer; Daniëlle A M Heideman Journal: Gynecol Oncol Date: 2016-03-03 Impact factor: 5.482
Authors: Roosmarijn Luttmer; Lise M A De Strooper; Maaike G Dijkstra; Johannes Berkhof; Peter J F Snijders; Renske D M Steenbergen; Folkert J van Kemenade; Lawrence Rozendaal; Theo J M Helmerhorst; René H M Verheijen; W Abraham Ter Harmsel; W Marchien van Baal; Peppino G C M Graziosi; Wim G V Quint; Johan W M Spruijt; Dorenda K E van Dijken; Daniëlle A M Heideman; Chris J L M Meijer Journal: Br J Cancer Date: 2016-07-14 Impact factor: 7.640
Authors: Mert Ulaş Barut; Ahmet Kale; Umur Kuyumcuoğlu; Murat Bozkurt; Elif Ağaçayak; Server Özekinci; Talip Gül Journal: Med Sci Monit Date: 2015-12-10