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
Year: 2025
Type: article
Study design: Observational Study
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.
Source: EBioMedicine
Authors: Valentine Marie Ferré, Axelle Dupont, Mélanie Draullette, Emy Valette, Gilles Collin, Margot Bucau, Laurent Siproudhis, Ghislain Staumont, Carine Roy, Albertus Theodorus Hesselink, Dominique Bouchard, Sylvie Radenne, Lucas Spindler, Anas Naji, Christine Bergeron, Anne Couvelard, Diane Descamps, Renske D.M. Steenbergen, Charlotte Charpentier, Laurent Abramowitz, Brochard Charlène, Lion Annie, Boutoille Hélène, Pillant-Le Moult Hélène, Soudan Denis, Lafferre Emilie, Eleout Kaplan Marianne, Favreau-Weltzer Charlotte, Hemery Philippe, Roumeguere Pauline, Faucher Zaegel Olivia, Enfredj Paul, Ganansia Roland, De Parades Vincent, Castinel Alain, Zaleski-Benfredj Annick, Meurette Guillaume, Fathallah Nadia, Wallenhorst Timothee, Rentien Anne Laure, Wemmert Charlotte, Zallot Camille, Cordonnier Carole, Pommaret Elise, Fellous Katia, El Mituialy Ahlem, Chapoutot Christian, Laclotte Cécile, Safa Far Eric, Laroche Helene, Ressiot Emmanuelle, Gorez Etienne, Suduca Jean-Michel, Delasalle Patrick
Institutions: Inserm, Université Paris Cité, Université Sorbonne Paris Nord, Assistance Publique – Hôpitaux de Paris, Hôpital Bichat-Claude-Bernard, Infection, Anti-microbiens, Modélisation, Evolution, Centre d'Investigation Clinique Bichat, Centre Hospitalier Universitaire de Rennes, Université de Rennes, Centre Hospitalier Universitaire de Toulouse, Self-screen BV (Netherlands), Maison de Sante Protestante de Bordeaux-Bagatelle, Lyon 1 Université, Hôpital de la Croix-Rousse, Hôpital Paris Saint-Joseph, Cancer Center Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,780
Award: G31754186
OpenAlex ID: W4414517768