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

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

doi:10.1186/s12885-023-11518-6

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

BMC Cancer. 2023 Nov 6;23(1):1072. doi: 10.1186/s12885-023-11518-6.

Authors

Alexandra Bukowski¹, Cathrine Hoyo², Nadja A Vielot³, Misa Graff⁴, Michael R Kosorok⁵, Wendy R Brewster^{4

6}, Rachel L Maguire^{2

7}, Susan K Murphy⁷, Belinda Nedjai⁸, Efthymios Ladoukakis⁸, Kari E North⁴, Jennifer S Smith^{4

9}

Affiliations

¹ Department of Epidemiology, University of North Carolina at Chapel Hill, 60 Bondurant Hall, Chapel Hill, NC, 27599, USA. alexandra_bukowski@med.unc.edu.
² Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA.
³ Department of Family Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill, 60 Bondurant Hall, Chapel Hill, NC, 27599, USA.
⁵ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁶ Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁷ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, 27701, USA.
⁸ Centre for Prevention, Detection and Diagnosis, Wolfson Institute of Population Health, Queen Mary University London, London, UK.
⁹ University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 27599, USA.

Abstract

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.

Keywords: Cancer risk; Cancer surveillance and screening; Cervical cancer; DNA methylation; Epigenetics; Epigenomics; Pre-neoplasia.

MeSH terms

Adult
Cell Adhesion Molecule-1 / genetics
DNA Methylation
Early Detection of Cancer
Epigenome
Female
Humans
Papillomaviridae / genetics
Papillomavirus Infections* / complications
Prospective Studies
United States
Uterine Cervical Dysplasia* / diagnosis
Uterine Cervical Neoplasms* / pathology

Substances

CADM1 protein, human
Cell Adhesion Molecule-1

Abstract

MeSH terms

Substances

Grants and funding