title: Associations between methylation of paternally expressed gene 3 (PEG3), cervical intraepithelial neoplasia and invasive cervical cancer.
abstract: Cytology-based screening for invasive cervical cancer (ICC) lacks sensitivity and specificity to discriminate between cervical intraepithelial neoplasia (CIN) likely to persist or progress from cases likely to resolve. Genome-wide approaches have been used to identify DNA methylation marks associated with CIN persistence or progression. However, associations between DNA methylation marks and CIN or ICC remain weak and inconsistent. Between 2008-2009, we conducted a hospital-based, case-control study among 213 Tanzania women with CIN 1/2/3 or ICC. We collected questionnaire data, biopsies, peripheral blood, cervical scrapes, Human papillomavirus (HPV) and HIV-1 infection status. We assessed PEG3 methylation status by bisulfite pyrosequencing. Multinomial logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI 95%) for associations between PEG3 methylation status and CIN or ICC. After adjusting for age, gravidity, hormonal contraceptive use and HPV infection, a 5% increase in PEG3 DNA methylation was associated with increased risk for ICC (OR = 1.6; 95% CI 1.2-2.1). HPV infection was associated with a higher risk of CIN1-3 (OR = 15.7; 95% CI 5.7-48.6) and ICC (OR = 29.5, 95% CI 6.3-38.4). Infection with high risk HPV was correlated with mean PEG3 differentially methylated regions (DMRs) methylation (r = 0.34 p<0.0001), while the correlation with low risk HPV infection was weaker (r = 0.16 p = 0.047). Although small sample size limits inference, these data support that PEG3 methylation status has potential as a molecular target for inclusion in CIN screening to improve prediction of progression. Impact statement: We present the first evidence that aberrant methylation of the PEG3 DMR is an important co-factor in the development of Invasive cervical carcinoma (ICC), especially among women infected with high risk HPV. Our results show that a five percent increase in DNA methylation of PEG3 is associated with a 1.6-fold increase ICC risk. Suggesting PEG3 methylation status may be useful as a molecular marker for CIN screening to improve prediction of cases likely to progress.
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors: Monica D
authors: MD
authors: Nye
authors: Cathrine
authors: C
authors: Hoyo
authors: Zhiqing
authors: Z
authors: Huang
authors: Adriana C
authors: AC
authors: Vidal
authors: Frances
authors: F
authors: Wang
authors: Francine
authors: F
authors: Overcash
authors: Jennifer S
authors: JS
authors: Smith
authors: Brandi
authors: B
authors: Vasquez
authors: Brenda
authors: B
authors: Hernandez
authors: Britta
authors: B
authors: Swai
authors: Olola
authors: O
authors: Oneko
authors: Pendo
authors: P
authors: Mlay
authors: Joseph
authors: J
authors: Obure
authors: Marilie D
authors: MD
authors: Gammon
authors: John A
authors: JA
authors: Bartlett
authors: Susan K
authors: SK
authors: Murphy
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D019175:DNA Methylation; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D016015:Logistic Models; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D016017:Odds Ratio; D030361:Papillomavirus Infections / Q000821:virology; D011379:Prognosis; D012307:Risk Factors; D013636:Tanzania; D002583:Uterine Cervical Neoplasms / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000150:complications / Q000175:diagnosis / Q000235:genetics*
chemical_list: D051741:Kruppel-Like Transcription Factors; C490820:PEG3 protein, human