J Gynecol Oncol.  2017 Jul;28(4):e56. 10.3802/jgo.2017.28.e56.

Genotype-specific methylation of HPV in cervical intraepithelial neoplasia

• Hsu YW
• Huang RL
• Su PH
• Chen YC
• Wang HC
• Liao CC
• Lai HC

• KMID: 2413439
• DOI: http://doi.org/10.3802/jgo.2017.28.e56

Abstract

OBJECTIVE
Hypermethylation of human papillomavirus (HPV) and host genes has been reported in cervical cancer. However, the degree of methylation of different HPV types relative to the severity of the cervical lesions remains controversial. Studies of the degree of methylation associated with the host gene and the HPV genome to the severity of cervical lesions are rare. We examined the association of methylation status between host genes and late gene 1 (L1) regions of HPV16, 18, 52, and 58 in cervical brushings.
METHODS
Cervical brushings from 147 HPV-infected patients were obtained. The samples comprised normal (n=28), cervical intraepithelial neoplasia (CIN) 1 (n=45), CIN2 (n=13), and CIN3/carcinoma in situ (n=61). The methylation status of HPV and host genes was measured using bisulfite pyrosequencing and quantitative methylation-specific polymerase chain reaction (PCR).
RESULTS
The degree of methylation of L1 in HPV16, 18, and 52 was associated with the severity of the cervical lesion. In HPV52, C-phosphate-G (CpG) sites 6368m, 6405m, and 6443m showed significantly higher methylation in lesions ≥CIN3 (p=0.005, 0.003, and 0.026, respectively). Methylation of most HPV types except HPV52 (r<−0.1) was positively correlated with the degree of methylation of host genes including PAX1 and SOX1 (0.4≤r≤0.7). Combining HPV methylation with PAX1 methylation improved the clustering for ≥CIN2.
CONCLUSION
Our study showed that the degree of L1 methylation of HPV16, 18, and 52 but not 58 is associated with the severity of cervical lesions. The association between HPV methylation and host gene methylation suggests different responses of host cellular epigenetic machinery to different HPV genotypes.

Keyword

DNA Methylation; Viruses; Methylation; PAX1 Transcription Factor; Cervical Intraepithelial Neoplasia; Human Papillomavirus 16; Human Papilloma Virus

MeSH Terms

Alphapapillomavirus/genetics
Biomarkers, Tumor/genetics
Cervical Intraepithelial Neoplasia/diagnosis/genetics/*virology
CpG Islands
*DNA Methylation
DNA, Viral/*metabolism
Early Detection of Cancer
Epigenesis, Genetic
Female
Genotype
Human Papillomavirus DNA Tests
Human papillomavirus 16/*genetics
Human papillomavirus 18/*genetics
Humans
Paired Box Transcription Factors/genetics
Papillomavirus Infections/complications/*genetics
ROC Curve
SOXB1 Transcription Factors/genetics
Biomarkers, Tumor
DNA, Viral
Paired Box Transcription Factors
SOXB1 Transcription Factors