Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States
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 +) fol...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-023-11518-6 |
| _version_ | 1797630194055380992 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Alexandra Bukowski |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T11:04:44Z |
| format | Article |
| id | doaj.art-cd758b948d6842b09caefb3e7cdf5eb7 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-03-11T11:04:44Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-cd758b948d6842b09caefb3e7cdf5eb72023-11-12T12:20:16ZengBMCBMC Cancer1471-24072023-11-0123111410.1186/s12885-023-11518-6Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United StatesAlexandra Bukowski0Cathrine Hoyo1Nadja A. Vielot2Misa Graff3Michael R. Kosorok4Wendy R. Brewster5Rachel L. Maguire6Susan K. Murphy7Belinda Nedjai8Efthymios Ladoukakis9Kari E. North10Jennifer S. Smith11Department of Epidemiology, University of North Carolina at Chapel HillDepartment of Biological Sciences, Center for Human Health and the Environment, North Carolina State UniversityDepartment of Family Medicine, University of North Carolina at Chapel HillDepartment of Epidemiology, University of North Carolina at Chapel HillDepartment of Biostatistics, University of North Carolina at Chapel HillDepartment of Epidemiology, University of North Carolina at Chapel HillDepartment of Biological Sciences, Center for Human Health and the Environment, North Carolina State UniversityDepartment of Obstetrics and Gynecology, Duke University Medical CenterCentre for Prevention, Detection and Diagnosis, Wolfson Institute of Population Health, Queen Mary University LondonCentre for Prevention, Detection and Diagnosis, Wolfson Institute of Population Health, Queen Mary University LondonDepartment of Epidemiology, University of North Carolina at Chapel HillDepartment of Epidemiology, University of North Carolina at Chapel HillAbstract 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.https://doi.org/10.1186/s12885-023-11518-6Cervical cancerCancer surveillance and screeningDNA methylationEpigenomicsEpigeneticsCancer risk |
| spellingShingle | 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 Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States BMC Cancer Cervical cancer Cancer surveillance and screening DNA methylation Epigenomics Epigenetics Cancer risk |
| title | Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States |
| title_full | Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States |
| title_fullStr | Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States |
| title_full_unstemmed | Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States |
| title_short | Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States |
| title_sort | epigenome wide methylation and progression to high grade cervical intraepithelial neoplasia cin2 a prospective cohort study in the united states |
| topic | Cervical cancer Cancer surveillance and screening DNA methylation Epigenomics Epigenetics Cancer risk |
| url | https://doi.org/10.1186/s12885-023-11518-6 |
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