61 DNA methylation markers for endometrial cancer Table 2: (Continued) Gene AUC (95% CI) Sensitivity % Specificity % Cytological sample type Study (year) Ref. MME 0.86 (0.76 – 0.96) U U Endometrial brushes Wentzensen (2014) (27) NPY 0.67 (U) U U Vaginal tampons BakkumGamez (2015) (25) NPY 0.60 (U) U U Endometrial brushes BakkumGamez (2015) (25) NPY 0.76 (0.64 – 0.88) U U Endometrial brushes Wentzensen (2014) (27) POU4F3 0.80 (0.7 – 0.9) 83.0 69.0 Cervical scrapes Chang (2018) (16) RASSF1 0.86 (U) U U Endometrial brushes BakkumGamez (2015) (25) RASSF1 0.79 (U) U U Vaginal tampons BakkumGamez (2015) (25) RASSF1 U (U) 40.0 100 Vaginal tampons Sangtani (2020) (26) TBX5 0.70 (U) U U Cervical scrapes Liew (2019) (13) ZNF662 0.89 (0.83 – 0.95) 92.0 80.0 Cervical scrapes Huang (2017) (24) †AUC separately calculated for Stage Ia (0.91) and Stage Ib/II/III (0.97). Markers with high performance (AUC ≥ 0.80) are marked in bold. AUC = Area under the curve; CI = Confidence interval; U = Unknown. The performance of DNA methylation marker panels for EC detection in minimally invasive samples is summarized in Table 3. The gene panels investigated include BHLHE22/CDO1 (13), BHLHE22/CDO1/CELF4 (24), BHLHE22/CDO1/HAND2 (13), BHLHE22/ CDO1/TBX5 (13), CADM1/MAL/miR124-2 (30) and HOXA9/RASSF1/HTR1B (26), with reported sensitivity and specificity values ranging from 60.0 - 91.8% and 70 - 100%, respectively. Table 3: DNA methylation marker panels for endometrial cancer detection with combined AUC, sensitivity and specificity values. Gene panel AUC Sensitivity % Specificity % Study (year) Ref. BHLHE22 / CDO1 U 84.8 88.0 Liew (2019) (13) BHLHE22 / CDO1 / CELF4 U 91.8 95.5 Huang (2017) (24) BHLHE22 / CDO1 / HAND2 U 87.0 86.0 Liew (2019) (13) BHLHE22 / CDO1 / TBX5 U 89.1 80.0 Liew (2019) (13) CADM1 / MAL / miR124-2 U 76.2 80.8† De Strooper (2014) (30) HOXA9 / HTR1B / RASSF1 U 60.0 100 Sangtani (2020) (26) †Specificity described for human papilloma virus (HPV)-positive and -negative women with low-grade cervical intraepithelial neoplasia (<CIN2). AUC = area under the curve; U = unknown. 3
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