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 statementWe 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.
Highlights
Half a million women throughout the world are diagnosed with cervical cancer annually and slightly over half of these women die from the disease; 80% are diagnosed in resourcepoor settings [1]
Our key findings in this case-control study of Tanzanian women are that after adjusting for Human papillomavirus (HPV) infection, age, oral contraceptive (OC) use, and HIV1 status, a 5% increase in DNA methylation at the Paternally Expressed Gene 3 (PEG3) differentially methylated regions (DMRs) was associated with a 1.6 fold increase in invasive cervical cancer (ICC) risk
We found that PEG3 DMR hypermethylation was correlated with HPV infection; a correlation that was stronger for high risk as compared to low risk HPV infection
Summary
Half a million women throughout the world are diagnosed with cervical cancer annually and slightly over half of these women die from the disease; 80% are diagnosed in resourcepoor settings [1]. Human papillomavirus (HPV), the only known etiologic agent for ICC, has been used to further stratify CIN cases from women with normal cytology, with high sensitivity [2] but low specificity. Approximately 4–10% of women with normal cytology are HPV DNA positive, and the sensitivity and specificity for HPV DNA testing remains suboptimal, resulting in a nonnegligible number of women with false positive results, requiring follow-up at cost to both the health care system and the patient. Suboptimal sensitivity and specificity has been shown to decrease adherence to recommended follow-up visits [3]. Identifying specific molecular features that can improve prediction of which CIN cases are likely to progress to ICC remains a priority
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