Abstract
IntroductionAlthough most invasive cervical cancer (ICC) harbor <20 human papillomavirus (HPV) genotypes, use of HPV screening to predict ICC from HPV has low specificity, resulting in multiple and costly follow-up visits and overtreatment. We examined DNA methylation at regulatory regions of imprinted genes in relation to ICC and its precursor lesions to determine if methylation profiles are associated with progression of HPV-positive lesions to ICC.Materials and methodsWe enrolled 148 controls, 38 CIN and 48 ICC cases at Kilimanjaro Christian Medical Centre from 2008 to 2009. HPV was genotyped by linear array and HIV-1 serostatus was tested by two rapid HIV tests. DNA methylation was measured by bisulfite pyrosequencing at regions regulating eight imprinted domains. Logistic regression models were used to estimate odd ratios.ResultsAfter adjusting for age, HPV infection, parity, hormonal contraceptive use, and HIV-1 serostatus, a 10 % decrease in methylation levels at an intragenic region of IGF2 was associated with higher risk of ICC (OR 2.00, 95 % CI 1.14–3.44) and cervical intraepithelial neoplasia (CIN) (OR 1.51, 95 % CI 1.00–2.50). Methylation levels at the H19 DMR and PEG1/MEST were also associated with ICC risk (OR 1.51, 95 % CI 0.90–2.53, and OR 1.44, 95 % CI 0.90–2.35, respectively). Restricting analyses to women >30 years further strengthened these associations.ConclusionsWhile the small sample size limits inference, these findings show that altered DNA methylation at imprinted domains including IGF2/H19 and PEG1/MEST may mediate the association between HPV and ICC risk.
Highlights
Most invasive cervical cancer (ICC) harbor \20 human papillomavirus (HPV) genotypes, use of HPV screening to predict ICC from HPV has low specificity, resulting in multiple and costly follow-up visits and overtreatment
After adjusting for age, HPV infection, parity, hormonal contraceptive use, and HIV-1 serostatus, a 10 % decrease in methylation levels at an intragenic region of Insulin-like growth factor 2 gene (IGF2) was associated with higher risk of ICC and cervical intraepithelial neoplasia (CIN)
Methylation levels at the H19 Differentially methylated regions (DMRs) and PEG1/MEST were associated with ICC risk
Summary
Most invasive cervical cancer (ICC) harbor \20 human papillomavirus (HPV) genotypes, use of HPV screening to predict ICC from HPV has low specificity, resulting in multiple and costly follow-up visits and overtreatment. We examined DNA methylation at regulatory regions of imprinted genes in relation to ICC and its precursor lesions to determine if methylation profiles are associated with progression of HPV-positive lesions to ICC. Current screening guidelines recommend liquid-based cytology screening methods followed by testing for HR-HPV genotypes, since most ICCs evolve slowly and harbor HR-HPV genotypes [4]. The sensitivity and specificity of existing screening tests remains suboptimal, leading to false positives and overtreatment which have been linked to subfertility and cervical stenosis [5]. Molecular features that together with known environmental factors can improve prediction of progression of cervical intraepithelial neoplasia (CIN) to ICC, are required
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