A Predictive Model Using Six Genes DNA Methylation Markers to Identify Individuals With High Risks of High-Grade Squamous Intraepithelial Lesions and Cervical Cancer

Hui Ding,1– 3,* Zhonghe Ke,4,* Xiao Xiao,4,5 Beibei Xin,6 Hui Xiong,7 Wen Lu1,8,9 1Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, People’s Republic of China; 2Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, People’s Republic of China; 3Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, People’s Republic of China; 4Department of Research and Development, Shanghai Rightongene Biotechnology Co. Ltd, Shanghai, 201403, People’s Republic of China; 5School of Physics, Changchun University of Science and Technology, Changchun, 130022, People’s Republic of China; 6Department of Medicine, Shanghai Rightongene Biotechnology Co. Ltd, Shanghai, 201403, People’s Republic of China; 7General Manager’s Office, Shanghai Rightongene Biotechnology Co. Ltd, Shanghai, 201403, People’s Republic of China; 8Department of Gynecology Oncology, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, People’s Republic of China; 9School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Lu, School of Medicine, Tongji University, No. 1239, Siping Road, Yangpu District, Shanghai, 200092, People’s Republic of China, Tel/Fax +86 021-20261000, Email [email protected]: Cervical cancer is preceded by low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Human papillomavirus (HPV) test is a sensitive method for cervical cancer screening, but it is less specific compared with cytological examination, leading to overtreatment and reduced patient compliance. Therefore, new detection methods that can improve the accuracy of cervical cancer screening are needed.Methods: In the present study, cervical exfoliated cell samples were collected from 228 Chinese individuals, including 114 healthy control individuals, 46 patients with LSIL, 21 patients with HSIL and 47 patients with cervical cancer. The DNA methylation levels of 12 cervical cancer-related genes were detected using quantitative multiplex methylation-specific PCR. All individuals were divided into high- or low-risk groups. Patients with HSIL and cervical cancer were assigned to the high-risk group, whereas healthy controls and patients with LSIL were assigned to the low-risk group. The ability to predict cancer risks was evaluated using ROC curves and a predictive model for cancer risk was constructed by linear regression analysis.Results: The methylation levels were significantly higher for all 12 genes in individuals with cervical cancer or HSIL, compared with those in LSIL or normal group. Family with sequence similarity 19 member A4 (FAM19A4), phosphatase and actin regulator 3 (PHACTR3), somatostatin (SST), Zic family member 1 (ZIC1), paired box 1 (PAX1) and zinc finger protein 671 (ZNF671) were used to construct a predictive model for cancer risk prediction, with a specificity of 89.6% and a sensitivity of 95.0%.Conclusion: The present study demonstrated the methylation levels of 12 cervical cancer-related genes were higher in Chinese patients with HSIL or cervical cancer. Also, a predictive model was constructed to distinguish cervical cancer or HSCL from individuals with low risk.Keywords: cervical cancer, high-grade squamous intraepithelial lesions, methylation, predictive model, cancer risk