Journal Article

Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States

Kosorok, Michael R., Maguire, Rachel L., Murphy, Susan K., Vielot, Nadja A., Graff, Misa, Ladoukakis, Efthymios, Bukowski, Alexandra, Brewster, Wendy R., Hoyo, Cathrine, Nedjai, Belinda, North, Kari E., Smith, Jennifer S.

2023

Overview

Background Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test. Methods A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K ( n  = 76) or EPIC 850K ( n  = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05. Results At enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2 , and APBB1IP . Conclusions Using prospective time-to-event data, we detected associations between CADM1 -, DAPK1 -, PAX1 -, and RARB -related CpGs and cervical disease progression, and we identified novel progression-associated CpGs. Impact Methylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Algorithms / Analysis / Biomarkers / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer / Cancer Research / Cancer risk / Cancer screening / Cancer surveillance and screening / Cell Adhesion Molecule-1 - genetics / Cellular biology / Censorship / Cervical cancer / Cervix dysplasia / Clinical decision making / Cohort analysis / Colposcopy / CpG islands / Death-associated protein kinase / Development and progression / Diagnosis / DNA Methylation / Early Detection of Cancer / Epigenetic inheritance / Epigenetics / Epigenome / Epigenomics / Female / Genes / Genomes / Health Promotion and Disease Prevention / Histology / Human papillomavirus / Humans / Medical records / Medical research / Medical screening / Medicine, Experimental / Medicine/Public Health / Methylation / Oncology / Papillomaviridae - genetics / Papillomavirus infections / Papillomavirus Infections - complications / Prospective Studies / Quality control / Sociodemographics / Surgical Oncology / Surveillance / Tissue inhibitor of metalloproteinase 2 / United States / Uterine Cervical Dysplasia - diagnosis / Uterine Cervical Neoplasms - pathology