Combined CADM1/MAL Methylation and Cytology Testing for Colposcopy Triage of High-Risk HPV-Positive Women

Abstract

Primary screening for high-risk human papillomavirus (hrHPV) requires a triage protocol. Repeat cytology testing at baseline and after 6 to 12 months has emerged as a reasonable triage approach, but carries the risk of loss to follow-up. Repeat cytology testing may be omitted if cytology is supplemented with another, complementary triage test at baseline. In this study, the performance of combined triage by cytology and DNA methylation analysis was assessed. In hrHPV-positive cervical scrapes (n ¼ 250), cytology [threshold: atypical squamous cells of undetermined significance (ASCUS)], bi-marker CADM1/MAL methylation testing (at different assay thresholds), and combinations of both were evaluated for endpoints cervical intraepithelial neoplasia grade 2 or worse (CIN2

Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up

“…Methylation levels of these genes in cervical scrapes increase with the severity of underlying cervical lesion 22, 25. Of interest, FAM19A4 methylation analysis detects (virtually) all cervical carcinomas, and has proven to be more sensitive than cytology for the detection of CIN3 lesions with a longer duration of existence 27. In fact, FAM19A4 methylation analysis tested positive in all cervical scrapes of women with CIN3 lesions with a duration of the associated HPV infection of >5 years 22.…”

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

“…Regardless of age, the NPV of FAM19A4 methylation analysis for ≥CIN3 was relatively consistent, ranging between 91.2% and 95.3% [51]. Combined methylation analysis of both CADM1/MAL on hrHPV-positive cervical scrapes has yielded a comparable accuracy in hrHPV-positive scrapes of screening attendees (n = 234 [102]) and non-attendees (n = 364 [107], Table 1), with a ≥CIN3 sensitivity of 68.4-69.4% and a corresponding specificity of 71.2-75.5%.…”

“…Therefore, host cell DNA methylation analysis might be of value as a marker for the detection of cervical (pre)cancer among hrHPV-positive women [32,92]. A variety of methylation markers has been studied in clinical cohorts of hrHPVpositive women [51,80,81,96,97,99,[102][103][104][105][106]. In general, these studies were cross-sectional or had a short-term follow-up and the majority of studies were performed in nonscreening cohorts.…”

“…A few studies have evaluated the accuracy of methylation analysis (CADM1/MAL, FAM19A4) combined with Pap cytology (Table 3) [102,107]. In both a screening [102] and a non-attendee population [107], CADM1/MAL methylation analysis combined with Pap cytology yielded a high sensitivity for ≥CIN3 of 86.8-88.7% with a corresponding specificity of 53.6-64.8% (Table 3).…”

“…In both a screening [102] and a non-attendee population [107], CADM1/MAL methylation analysis combined with Pap cytology yielded a high sensitivity for ≥CIN3 of 86.8-88.7% with a corresponding specificity of 53.6-64.8% (Table 3). In a gynecologic outpatient population, combined FAM19A4 methylation analysis with Pap cytology had a sensitivity of 96.7%, however with a relatively low specificity of 32.2% among women ≥30 years of age [51].…”