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Cervical cancer is the fourth most common malignancy affecting women worldwide. The development of disease is related to high-risk human papillomavirus (hrHPV) infection. Cytology has been the most recommended triage for primary cervical (pre)cancer screening despite relatively low sensitivity. Recently, genomic DNA methylation has been proposed as an additional marker to increase sensitivity for detecting cervical precancerous lesion. This study aimed to evaluate the performance of methylation status of three tumor suppressor genes ( CADM1 ,  FAM19A4 , and  MAL ) and HPV genotyping in detection of cytologic and histologic abnormalities in cervical cancer screening. Two hundred and sixty samples with available frozen cell pellets including 70 randomly selected cases of negative for intraepithelial lesion or malignancy (NILM)&HPV-negative, 70 randomly selected cases of NILM&HPV-positive, and 120 cytologic abnormalities & HPV-positive from a population-based cervical cancer screening program (n = 7,604) were investigated for the DNA methylation pattern of  CADM1 ,  FAM19A4 , and  MAL . Of 120 cytologic abnormalities & HPV-positive cases, there were 115 available histologic results. HPV52 and HPV58 were most commonly found in histologic HSIL+. The methylation levels of  CADM1 ,  FAM19A4 , and  MAL  were elevated with the severity of cytologic abnormality which significantly increased by 3.37, 6.65 and 2 folds, respectively, in cytologic HSIL comparing with NILM. A significant increase in methylation levels of these three genes was also observed in histologic HSIL+ compared with negative histology but only  CADM1  showed a significant higher methylation level than histologic LSIL. Using the ROC curve analysis, DNA methylation levels of  FAM19A4  performed best in differentiating high-grade cytology (ASC-H+ from NILM/ASC-US/LSIL), followed by  CADM1  and  MAL . Whilst the  CADM1  methylation performed best in distinguishing histologic HSIL+ from negative/LSIL with an area under the ROC curve of 0.684, followed by  MAL  (0.663) and  FAM19A4  (0.642). Interestingly, after combining high DNA methylation levels to HPV16/18 genotypes, rates of histologic HSIL+ detection were substantially increased from 25% to 79.55% for  CADM1 , 77.27% for  FAM19A4 , and 72.73% for  MAL , respectively. The rate further increased up to 95.45% when at least one of three genes had a high methylation level. This suggests a possible role of genomic DNA methylation, especially  CADM1 , in detecting histologic HSIL+ lesions in combination with hrHPV testing.

Role of genomic DNA methylation in detection of cytologic and histologic abnormalities in high risk HPV-infected women