Theranostics 2019; 9(24):7251-7267. doi:10.7150/thno.31155

Research Paper

DNA methylation-driven genes for constructing diagnostic, prognostic, and recurrence models for hepatocellular carcinoma

Junyu Long1,#, Peipei Chen2,#, Jianzhen Lin1,#, Yi Bai1, Xu Yang1, Jin Bian1, Yu Lin3, Dongxu Wang1, Xiaobo Yang1, Yongchang Zheng1,✉, Xinting Sang1,✉, Haitao Zhao1,✉

1. Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
2. Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
3. Shenzhen Withsum Technology Limited, Shenzhen, China
#These authors contributed equally to this work

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Citation:
Long J, Chen P, Lin J, Bai Y, Yang X, Bian J, Lin Y, Wang D, Yang X, Zheng Y, Sang X, Zhao H. DNA methylation-driven genes for constructing diagnostic, prognostic, and recurrence models for hepatocellular carcinoma. Theranostics 2019; 9(24):7251-7267. doi:10.7150/thno.31155. Available from http://www.thno.org/v09p7251.htm

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Abstract

In this study, we performed a comprehensively analysis of gene expression and DNA methylation data to establish diagnostic, prognostic, and recurrence models for hepatocellular carcinoma (HCC).

Methods: We collected gene expression and DNA methylation datasets for over 1,200 clinical samples. Integrated analyses of RNA-sequencing and DNA methylation data were performed to identify DNA methylation-driven genes. These genes were utilized in univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to build a prognostic model. Recurrence and diagnostic models for HCC were also constructed using the same genes.

Results: A total of 123 DNA methylation-driven genes were identified. Two of these genes (SPP1 and LCAT) were chosen to construct the prognostic model. The high-risk group showed a markedly unfavorable prognosis compared to the low-risk group in both training (HR = 2.81; P < 0.001) and validation (HR = 3.06; P < 0.001) datasets. Multivariate Cox regression analysis indicated the prognostic model to be an independent predictor of prognosis (P < 0.05). Also, the recurrence model successfully distinguished the HCC recurrence rate between the high-risk and low-risk groups in both training (HR = 2.22; P < 0.001) and validation (HR = 2; P < 0.01) datasets. The two diagnostic models provided high accuracy for distinguishing HCC from normal samples and dysplastic nodules in the training and validation datasets, respectively.

Conclusions: We identified and validated prognostic, recurrence, and diagnostic models that were constructed using two DNA methylation-driven genes in HCC. The results obtained by integrating multidimensional genomic data offer novel research directions for HCC biomarkers and new possibilities for individualized treatment of patients with HCC.

Keywords: DNA methylation-driven genes, hepatocellular carcinoma, diagnosis, prognosis, recurrence