Table 1.
Overview of commercial or research host cell DNA methylation assays and their performance for the detection of CIN3 or worse in cervical scrapes or self‐collected specimens in different clinical settings
| Marker (panel) | Assay | Reference | HPV | Sample type | n | CIN3 (%) | ICC (%) | Sens. | Spec. | NPV | PPV | Comment | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Screening populations | |||||||||||||
| FAM19A4/miR124‐2 | QMSP | Bonde, subm. | HPV+ | Cervical scrapes | 2384 | 228 (9.6%) | 20 (0.8%) | 77.2 | 78.3 | 96.9 | 28.3 | End point CIN3; European screening populations | |
| FAM19A4/miR124‐2 | QMSP | [70] | HPV+ | Cervical scrapes | 979 | 109 (11.1%) | 6 (0.6%) | 71.3 | 78.3 | 94.8 | 33.0 | Cross‐sectional data | |
| — | — | 87.2 | — | 14‐year NPV | |||||||||
| FAM19A4/miR124‐2 | QMSP | [69] | HPV+ | Cervical scrapes | 1025 | 192 (18.7%) | 19 (1.9%) | — | — | 83.7 | 60.2 | 14‐year NPV and PPV | |
| CADM1/MAL | QMSP | [63] | HPV+ | Cervical scrapes | 234 | 38 (16.2%) | 3 (1.3%) | 68.4 | 75.5 | 92.5 | 35.1 | Consecutive series from screening cohort | |
| EPB41L3/HPV16L1/HPV16L2/HPV18L2/HPV31L1/HPV33L2* | PSQ | [34] | HPV+ | Cervical scrapes | 257 | 44 (17.1%) | 8 (3.1%) | 93.2 | 41.8 | — | 24.8 | Case–control within screening cohort; end point CIN3 | |
| EPB41L3/HPV16L1/HPV16L2/HPV18L2/HPV31L1/HPV33L2* | PSQ | [65] | HPV+ | Cervical scrapes | 341 | 18 (5.3%) | 1 (0.3%) | 84 | 63 | — | — | Selection of women from screening cohort; CIN2 (n = 20) lesions were excluded from analyses | |
| Non‐attendee population | |||||||||||||
| FAM19A4/miR124‐2 | QMSP | [28] | HPV+ | Self‐samples (brushes) | 254 | 68 (26.8%) | 4 (1.6%) | 69.4 | 76.4 | 86.3 | 53.8 | Performance data from validation set; brush‐ and lavage‐collected samples from (mostly) same patients | |
| Self‐samples (lavage) | 389 | 72 (18.5%) | 6 (1.5%) | 70.5 | 67.8 | 90.2 | 35.5 | ||||||
| CADM1/MAL | QMSP | [33] | HPV+ | Cervical scrapes | 364 | 56 (15.4%) | 6 (1.6%) | 69.4 | 71.2 | 91.9 | 33.1 | ||
| Gynaecological referral populations/Selection of archived material | |||||||||||||
| FAM19A4/miR124‐2 | QMSP | [30] | HPV+/− | Cervical scrapes | 538 | 66 (12.3%) | 6 (1.1%) | 77.8** | 69.3** | 98.3 ** | 36.4 ** | Women with abnormal cytology referred for colposcopy | |
| CADM1/MAL/miR124‐2 | QMSP | [27] | HPV+ | Cervical scrapes | 247 | 16 (6.5%) | 79 (32.0%) | 94.7 | 78.9 | — | — | Selection of archived material | |
| EPB41L3/HPV16L1/HPV16L2/HPV18L2/HPV31L1/HPV33L2** | PSQ | [68] | HPV+ | Cervical scrapes | 1493 | 373 (25.0%) | — | 90 | 49 | — | 51 | Women with abnormal cytology referred for colposcopy; end point CIN2/3 (n = 556) | |
| ASTN1/DLX1/ITGA4/RXFP3/SOX17/ZNF671 | QMSP | [37] | HPV+/− | Cervical scrapes | 280 | 50 (17.9%) | 5 (1.8%) | 64.8** | 94.6** | 91.7** | 74.5** | Residual samples from routine screening (NILM cytology) and from patients with CIN1+ on histology | |
| ASTN1/DLX1/ITGA4/RXFP3/SOX17/ZNF671 | QMSP | [39] | HPV+/− | Cervical scrapes | 306 | 88 (28.8%) | 5 (1.6%) | 67.7** | 82.6** | — | — | Women referred for colposcopy | |
| HPV+/− | 64.5 | 88.7 | — | — | |||||||||
| POU4F3 | QMSP | [40] | HPV+ | Cervical scrapes | 1287 | 65 (5.1%) | 12 (0.9%) | 89.6 | 60.9 | — | — | Mixed screening population and women referred for cone biopsy or hysterectomy; ICC cases included AIS and CIS | |
| PAX1 | QMSP | [44] | HPV+/− | Cervical scrapes | 449 | 87 (19.4%) | 71 (15.8%) | 69.6** | 81.8** | — | — | ||
| PAX1 | QMSP | [42] | HPV+/− | Cervical scrapes | 346 | 42 (12.1%) | 30 (8.7%) | 64** | 91** | — | — | Women with low‐ or high‐grade cytology referred for colposcopy and controls from routine screening (NILM cytology) | |
| HPV+/− | 57 | 96 | — | — | |||||||||
| PAX1 | QMSP | [43] | HPV+/− | Cervical scrapes | 419 | 32 (7.6%) | 4 (1.0%) | 86** | 85** | — | — | Mixed screening population and women referred with abnormal cytology | |
| PAX1 | QMSP | [45] | HPV+/− | Cervical scrapes | 321 | 24 (7.5%) | 1 (0.3%) | 52.0** | 90.3** | — | — | Women with ASC‐US cytology referred for colposcopy | |
AIS, adenocarcinoma in situ; ASC‐US, atypical squamous cells of unknown significance; CIN, cervical carcinoma in situ; CIS, cervical intraepithelial neoplasia, graded 1–3; HPV, human papillomavirus; ICC, invasive cervical cancer; n, samples size; NILM, negative for intraepithelial lesion or malignancy; NPV, negative predictive value; PPV, positive predictive value; PSQ, pyrosequencing; QMSP, quantitative methylation‐specific polymerase chain reaction; Sens., sensitivity; Spec., specificity.
Combination of cellular and viral targets.
Performance evaluated independent of HPV result.