Hypermethylated CDO1 and ZNF454 in Cytological Specimens as Screening Biomarkers for Endometrial Cancer

Lei Wang; Lanlan Dong; Jun Xu; Lin Guo; Yiran Wang; Kangkang Wan; Wei Jing; Lanbo Zhao; Xue Feng; Kailu Zhang; Miao Guo; Yuliang Zou; Lianglu Zhang; Qiling Li

doi:10.3389/fonc.2022.714663

Hypermethylated CDO1 and ZNF454 in Cytological Specimens as Screening Biomarkers for Endometrial Cancer

Front Oncol. 2022 Apr 28:12:714663. doi: 10.3389/fonc.2022.714663. eCollection 2022.

Authors

Lei Wang¹, Lanlan Dong², Jun Xu², Lin Guo^{1

3}, Yiran Wang¹, Kangkang Wan², Wei Jing^{1

4}, Lanbo Zhao¹, Xue Feng¹, Kailu Zhang¹, Miao Guo¹, Yuliang Zou¹, Lianglu Zhang^{2

5}, Qiling Li¹

Affiliations

¹ Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
² Wuhan ammunition Life-Tech Co., Ltd., Wuhan, China.
³ Department of Obstetrics and Gynecology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China.
⁴ Department of Gynecologic Oncology, Shaanxi Provincial Cancer Hospital, Xi'an, China.
⁵ State Key Laboratory of Virology, Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, China.

Abstract

We aimed to estimate the diagnostic value of DNA methylation levels in cytological samples of endometrial cancer (EC) and atypical hyperplasia (AH). Two hypermethylated genes, namely, cysteine dioxygenase type 1 (CDO1) and zinc finger protein 454 (ZNF454), in patients with EC were identified from The Cancer Genome Atlas database. In 103 endometrial histological specimens (the training set), the methylation levels of candidate genes were verified by quantitative methylation-specific polymerase chain reaction (qMSP). The methylation levels of another 120 cytological specimens (the testing set) were evaluated. Sensitivity (Se), specificity (Sp), accuracy, and area under the curve (AUC) were determined, with diagnosis verified by histopathological results. CDO1 and ZNF454 verified hypermethylation in histological specimens of patients with EC and AH compared with those with benign and normal endometrium (P < 0.001). In cytological specimens, hypermethylated CDO1 showed 86.36% Se and 90.79% Sp with the cutoff value of 6.0 to distinguish between malignant and benign groups; ZNF454 showed 79.55% Se and 93.42% Sp with the cutoff value of 7.1. When the two genes were combined, Se increased to 90.91% and Sp was 86.84%. AUC reached 0.931 (95% CI: 0.885-0.976). The diagnostic accuracy with cytology had no significant difference with endometrial tissue (P = 0.847 for CDO1, P = 0.108 for ZNF454, and P = 0.665 for their combination). Hypermethylated CDO1 and ZNF454 in endometrial cytology showed high Se, Sp, and AUC to detect EC and AH. Methylation analysis of endometrial cytology is promising biomarker for the screening of EC and AH.

Keywords: DNA methylation; cysteine dioxygenase type 1 (CDO1); cytology; endometrial cancer (EC); endometrial cytology test (ECT); screening; zinc finger protein 454 (ZNF454).