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

Abstract

DNA methylation analysis of cervical scrapes using FAM19A4 and mir124‐2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV‐positive women. To date, longitudinal data on the cancer risk of methylation test‐negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124‐2 methylation analysis in an HPV‐positive screening cohort with 14 years of follow‐up. Archived HPV‐positive cervical scrapes of 1,040 women (age 29–61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124‐2 methylation. By linkage with the nationwide network and registry of histo‐ and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow‐up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124‐2 methylation, including 24 women with cervical cancer in follow‐up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow‐up. Within screening round capability of FAM19A4/mir124‐2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5–100). Kaplan–Meier estimate of 14‐year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66–3.0) among baseline methylation‐negative and 2.4% (95% CI: 1.4–3.6) among baseline cytology‐negative women (risk difference: 0.71% [95% CI: 0.16–1.4]). In conclusion, a negative FAM19A4/mir124‐2 methylation test provides a low cervical cancer risk in HPV‐positive women of 30 years and older. FAM19A4/mir124‐2 methylation testing merits consideration as an objective triage test in HPV‐based cervical screening programs.

Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124‐2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions

“…Currently available methylation markers have shown good clinical performance in the detection of advanced transforming precursor lesions and CC in hrHPV‐positive women. In addition, results from a large follow‐up study have shown a low CC risk for hrHPV‐positive women with a negative FAM19A4/miR124‐2 triage test result, offering an objective triage test in hrHPV‐based screening programs . We found that FAM19A4 has the major contribution to predicting the presence of HSIL/CIN3 as compared to miR124‐2.…”

Intra‐ and inter‐laboratory agreement of the FAM19A4/mir124‐2 methylation test: Results from an international study

“…Specimens with sufficient leftover material were randomly selected from local cohorts. It was verified within each test situation that the QIAsure Methylation Test positivity rate was comparable to the known positivity rate in an HPV‐positive screening cohort, that is, test situation 1:39%; test situation 2:30%; and test situation 3:31%.…”

“…A key aspect is the efficient detection of cervical carcinomas and advanced CIN lesions, that is, CIN2/3 lesions associated with a duration of the preceding hrHPV infection of >5 years, which have increased methylation levels and many chromosomal aberrations (“cancer‐like” (epi)genetic profile), and have therefore been considered to have an expected high short‐term risk of progression to cancer . A negative QIAsure Methylation Test, on the other hand, indicates a low cervical cancer risk over the subsequent 14 years in hrHPV‐positive women …”

Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial

“…In the HPV arms of the trial, S5 triage would have reduced clinician visits and screen tests as more high‐grade disease would have been detected at baseline, thus simplifying the screening algorithm and potentially reducing loss to follow‐up. In future, methylation markers may be shown to preferentially detect advanced lesions with a high short term risk of cervical cancer; indeed, a recent study from the POBASCAM trial showed that women negative for DNA methylation had a low future risk of cervical cancer over the subsequent 14 years …”