J Gynecol Oncol.  2016 Mar;27(2):e14. 10.3802/jgo.2016.27.e14.

DNA methylation in human papillomavirus-infected cervical cells is elevated in high-grade squamous intraepithelial lesions and cancer

• Kim MK
• Lee IH
• Lee KH
• Lee YK
• So KA
• Hong SR
• Hwang CS
• Kee MK
• Rhee JE
• Kang C
• Hur SY
• Park JS
• Kim TJ

• KMID: 2360244
• DOI: http://doi.org/10.3802/jgo.2016.27.e14

Abstract

OBJECTIVE
DNA methylation has been shown to be a potential biomarker for early cancer detection. The aim of this study was to evaluate DNA methylation profiles according to liquid-based Pap (LBP) test results and to assess their diagnostic value in a Korean population.
METHODS
A total of 205 patients with various Papanicolaou test results were enrolled to this study (negative, 26; atypical squamous cells of undetermined significance, 39; low grade squamous intraepithelial lesion, 44; high grade squamous intraepithelial lesion (HSIL), 48; and cancer, 48). DNA methylation analysis of four genes, ADCYAP1, PAX1, MAL, and CADM1, was performed on residual cervical cells from LBP samples using a quantitative bisulfite pyrosequencing method. To evaluate the diagnostic performance of the four methylated genes for cancer detection, receiver operating characteristic (ROC) curves were drawn. Sensitivities and specificities were also tested at cutoffs determined from the ROC curves.
RESULTS
Cervical cancer cells showed dramatically increased methylation levels for the four genes analyzed. ADCYAP1 and PAX1 also trended toward elevated methylation levels in HSIL samples, although the levels were much lower than those in cancer cells. The sensitivities of methylated ADCYAP1, PAX1, MAL, and CADM1 for the detection of cancer were 79.2%, 75.0%, 70.8%, and 52.1%, and the specificities were 92.0%, 94.0%, 94.7%, and 94.0%, respectively. Methylated ADCYAP1 and PAX1 demonstrated relatively better discriminatory ability than did methylated MAL and CADM1 (area under the curves 0.911 and 0.916 vs. 0.854 and 0.756, respectively).
CONCLUSION
DNA methylation status, especially in the ADCYAP1 and PAX1 genes, showed relatively good specificity, ranging from 90% to 94%. The possible additive and complementary roles of DNA methylation testing with respect to conventional cervical cancer screening programs will need to be validated in prospective population-based studies.

Keyword

Cervical Cancer Screening; Cervical Cytology; Cervical Intraepithelial Neoplasia; DNA Methylation; Uterine Cervical Neoplasms

MeSH Terms

Alphapapillomavirus/genetics
*Atypical Squamous Cells of the Cervix/pathology/virology
Cell Adhesion Molecules/genetics
*DNA Methylation
Female
Genotype
Humans
Immunoglobulins/genetics
Myelin and Lymphocyte-Associated Proteolipid Proteins/genetics
Paired Box Transcription Factors/genetics
Papanicolaou Test
Pituitary Adenylate Cyclase-Activating Polypeptide/genetics
ROC Curve
Squamous Intraepithelial Lesions of the Cervix/*genetics/pathology/virology
Uterine Cervical Neoplasms/*genetics/pathology/virology
Vaginal Smears
Cell Adhesion Molecules
Immunoglobulins
Myelin and Lymphocyte-Associated Proteolipid Proteins
Paired Box Transcription Factors
Pituitary Adenylate Cyclase-Activating Polypeptide