TY - JOUR
T1 - Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3
AU - Wentzensen, Nicolas
AU - Sun, Chang
AU - Ghosh, Arpita
AU - Kinney, Walter
AU - Mirabello, Lisa
AU - Wacholder, Sholom
AU - Shaber, Ruth
AU - Lamere, Brandon
AU - Clarke, Megan
AU - Lorincz, Attila T.
AU - Castle, Philip E.
AU - Schiffman, Mark
AU - Burk, Robert D.
N1 - Funding Information:
The research was funded by the Intramural Research Program of the National Cancer Institute. The funding source had no influence on the design, conduct, and evaluation of the study.
PY - 2012/11/21
Y1 - 2012/11/21
N2 - Background Persistent infections with carcinogenic human papillomavirus (HPV) types are the necessary cause of cervical cancer. We recently demonstrated that the HPV16 genome is strongly methylated in cervical precancer compared with transient infections. However, the extent of methylation in other HPV types and its role in progression to cancer is poorly understood.MethodsWe analyzed whole-genome methylation patterns of the three next most carcinogenic HPV genotypes: HPV31 (closely related to HPV16), and two other closely related types, HPV18 and HPV45. DNA was extracted from cervical cytology specimens from 92 women with precancer and 96 women infected with HPV31, HPV18, or HPV45, but who had no cytological or histological abnormalities. After bisulfite modification, genome-wide pyrosequencing was performed covering 80-106 sites. We calculated differences in median methylation, odds ratios, areas under the curve, and Spearman rank correlation coefficients for methylation levels between different sites. All statistical tests were two-sided.ResultsFor all three HPV types, we observed strongly elevated methylation levels at multiple CpG sites in the E2, L2, and L1 regions among women with cervical intraepithelial neoplasia grade 3 compared with women with transient infections. We observed high correlation of methylation patterns between phylogenetically related types. The highest areas under the curve were 0.81 for HPV31, 0.85 for HPV18, and 0.98 for HPV45. Differential methylation patterns in cervical intraepithelial neoplasia grade 3 patients with multiple infections suggest that methylation can clarify which of the infections is causal.Conclusions Carcinogenic HPV DNA methylation indicates transforming HPV infections. Our findings show that methylation of carcinogenic HPV types is a general phenomenon that warrants development of diagnostic assays.
AB - Background Persistent infections with carcinogenic human papillomavirus (HPV) types are the necessary cause of cervical cancer. We recently demonstrated that the HPV16 genome is strongly methylated in cervical precancer compared with transient infections. However, the extent of methylation in other HPV types and its role in progression to cancer is poorly understood.MethodsWe analyzed whole-genome methylation patterns of the three next most carcinogenic HPV genotypes: HPV31 (closely related to HPV16), and two other closely related types, HPV18 and HPV45. DNA was extracted from cervical cytology specimens from 92 women with precancer and 96 women infected with HPV31, HPV18, or HPV45, but who had no cytological or histological abnormalities. After bisulfite modification, genome-wide pyrosequencing was performed covering 80-106 sites. We calculated differences in median methylation, odds ratios, areas under the curve, and Spearman rank correlation coefficients for methylation levels between different sites. All statistical tests were two-sided.ResultsFor all three HPV types, we observed strongly elevated methylation levels at multiple CpG sites in the E2, L2, and L1 regions among women with cervical intraepithelial neoplasia grade 3 compared with women with transient infections. We observed high correlation of methylation patterns between phylogenetically related types. The highest areas under the curve were 0.81 for HPV31, 0.85 for HPV18, and 0.98 for HPV45. Differential methylation patterns in cervical intraepithelial neoplasia grade 3 patients with multiple infections suggest that methylation can clarify which of the infections is causal.Conclusions Carcinogenic HPV DNA methylation indicates transforming HPV infections. Our findings show that methylation of carcinogenic HPV types is a general phenomenon that warrants development of diagnostic assays.
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U2 - 10.1093/jnci/djs425
DO - 10.1093/jnci/djs425
M3 - Article
C2 - 23093560
AN - SCOPUS:84870170478
SN - 0027-8874
VL - 104
SP - 1738
EP - 1749
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 22
ER -