Abstract A24: IGF2/H19 and PEG1/MEST DNA methylation in CIN1, CIN2, CIN3 and cervical cancer in Tanzanian women: In search of disease progression biomarkers

Adriana C. Vidal, Monica Nye, Susan K. Murphy, Francine Overcash, Olola Oneko, John A. Bartlett, Zhiqing Huang, Pendo Mlay, Joseph Obure, Jennifer S. Smith, Brenda Hernandez, and Cathrine Hoyo
Publication year: 

Background: Epigenetic mechanisms have been hypothesized to be etiologically involved in progression of cervical intraepithelial neoplasia (CIN) to invasive cervical cancer (ICC), although empirical data are lacking.

Methods: We enrolled 148 controls, 38 CIN and 48 ICC cases at Kilimanjaro Christian Medical Centre from 2008-2009. HPV was genotyped by HPV linear array and HIV-1 serostatus was tested by two rapid HIV tests. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of IGF2/H19 and PEG1/MEST imprinted domains, using pyrosequencing. Logistic regression models were used to estimate odd ratios (ORs).

Results: After adjusting for age, HPV infection, parity, hormonal contraceptive use, and HIV-1 serostatus, a 10% decrease in methylation at the IGF2 CTCF3 DMR was associated with a significantly higher risk of ICC (OR=2.00, 95% CI 1.14-3.44) and CIN (OR=1.51, 95% CI 1.00-2.50). We observed similar, albeit weaker pattern of associations between the H19 DMR and ICC and PEG1/MEST (OR= 1.51, 95% CI 0.90-2.53, and OR= 1.44, 95% CI 0.90-2.35, respectively). Restricting analyses to older women (>30 years old) further strengthened these associations.

Conclusions: Aberrant DNA methylation at regulatory regions of imprinted genes may increase susceptibility to CIN and ICC and this association appears independent of HPV infection. While the small sample size limits inference, these findings support the hypothesis that DNA methylation at imprinted domains, including IGF2/H19 and PEG1/MEST, may represent susceptibility loci that can be exploited to identify, from among a large number of CIN, those likely to progress.