Clinical Diagnostic and Prognostic Potential of NDRG1 and NDRG2 in Hepatocellular Carcinoma Patients

Shaohua Xu; Ruihuan Gao; Yidan Zhou; Ying Yang; Yi Zhang; Qianyuan Li; Chunhua Luo; Song-Mei Liu

doi:10.3389/fonc.2022.862216

Clinical Diagnostic and Prognostic Potential of NDRG1 and NDRG2 in Hepatocellular Carcinoma Patients

Front Oncol. 2022 Jun 20:12:862216. doi: 10.3389/fonc.2022.862216. eCollection 2022.

Authors

Shaohua Xu¹, Ruihuan Gao¹, Yidan Zhou¹, Ying Yang¹, Yi Zhang¹, Qianyuan Li², Chunhua Luo², Song-Mei Liu¹

Affiliations

¹ Department of Clinical Laboratory, Center for Gene Diagnosis & Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China.
² The First College of Clinical Medical Science, Three Gorges University, Hubei, China.

Abstract

Background: Primary liver cancer is still the most common lethal malignancy. The N-myc downstream-regulated gene family (NDRG1-4) is a group of multifunctional proteins associated with carcinogenesis. However, systematic evaluation of the diagnostic and prognostic values of NDRG1 or NDRG2 expression in liver cancer is poorly investigated.

Method: The gene expression matrix of liver hepatocellular carcinoma (LIHC) was comprehensively analyzed by the "limma" and "Dseq2" R packages. The Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were used to identify the biological functional differences. A single-sample GSEA (ssGSEA) was conducted to quantify the extent of immune cell infiltration. Finally, the clinical and prognostic information of LIHC patients was systematically investigated using Kaplan-Meier analysis and logistic and Cox regression analysis.

Results: Compared with normal tissues, NDRG1 expression was higher, whereas NDRG2 expression was lower in tumor tissues (P <0.001). The area under the receiver operator characteristic curve (AUROC) of NDRG1 and NDRG2 for LIHC was 0.715 and 0.799, respectively. Kaplan-Meier analysis revealed that NDRG1 and NDRG2 were independent clinical prognostic biomarkers for the overall survival (OS, P = 0.001 and 2.9e-06), progression-free interval (PFI, P = 0.028 and 0.005) and disease-specific survival (DSS, P = 0.027 and P <0.001). The C-indexes and calibration plots of the nomogram suggest that NDRG1 and NDRG2 have an effective predictive performance for OS (C-index: 0.676), DSS (C-index: 0.741) and PFI (C-index: 0.630) of liver cancer patients. The mutation rate of NDRG1 in liver cancer reached up to 14%, and DNA methylation levels of NDRG1 and NDRG2 promoters correlated significantly with clinical prognosis.

Conclusions: The mRNA expression and DNA methylation of NDRG superfamily members have the potential for LIHC diagnosis and prognosis via integrative analysis from multiple cohorts.

Keywords: Kaplan–Meier; LIHC; NDRG1; NDRG2; hepatocellular carcinoma; methylation; prognosis.