DNA Methylation Markers ZNF582 and ASCL1 Predict Progression to Anal Cancer in High-Risk Patients
In a French national multicenter cohort of 514 patients with prior high-grade anal lesions followed for a median of 48 months, elevated ZNF582 and ASCL1 methylation levels on anal smears were significantly associated with progression to anal cancer in multivariable analysis. Both markers outperformed conventional markers including HPV status and cytology for predicting cancer at 1 and 3 years. This positions host-cell DNA methylation as a promising triage tool for prioritising high-resolution anoscopy in overburdened screening programmes.
The original study
Higher levels of host-cell DNA methylation markers ZNF582 and ASCL1 on anal smears are predictive for progression to anal cancer in patients with previous high-grade lesions.
- Authors
- Ferré VM, Dupont A, Draullette M, Valette E, Collin G, Bucau M, et al.
- Journal
- EBioMedicine
- Type
- Journal Article, Multicenter Study, Observational Study
- PMID
- 40997682
Original abstract
BACKGROUND: French and International anal cancer screening recommendations for at-risk populations, published in 2024, are based on cytology and/or high-risk human papillomavirus (HPV) detection on anal smears. Biological markers to triage the patients most at-risk for anal cancer are crucial in prioritising patients needing high-resolution anoscopy consultations, which are frequently overwhelmed. METHODS: The AIN3 cohort is a French national multicenter study including patients with a history of high-grade anal lesions (AIN3). Patients were followed-up for at least 3 years, with anal smears and clinical examinations performed yearly. Levels of ZNF582 and ASCL1 gene methylation were quantified using real-time PCR on anal smears collected at the time of inclusion. FINDINGS: Overall, 514 anal smears were contributive for host-cell DNA methylation analysis. Patients' mean age was 50.8 years and 40% were women. Among the 41% who were living with HIV, 91% were men. Median follow-up duration was 48 months, and 22 patients (4%) developed anal cancer during follow-up. Higher methylation levels of ZNF582 and ASCL1 were significantly associated with high-grade squamous cell intraepithelial lesion (HSIL) cytology, p16-Ki67 dual-staining positivity, and high-risk HPV and HPV16 positivity on the same anal smear. Both methylation markers showed an AUC of 0.72 for discrimination between HSIL and non-HSIL cytology on the same anal smear. Higher methylation levels of both markers were significantly associated with evolution to anal cancer in univariate and multivariable analyses adjusted for age and HIV status (p < 0.001). When assessing the AUC over 1 and 3 years of follow-up, methylation markers demonstrated superior predictive value for anal cancer compared to other markers. INTERPRETATION: We have demonstrated the predictive value of host-cell DNA methylation marker levels in anal smears with regard to evolution to anal cancer in a very high-risk population. FUNDING: This study was funded by the Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS) I Maladies Infectieuses Emergentes.