ZNF492 and GPR149 methylation patterns as prognostic markers for clear cell renal cell carcinoma: Array‑based DNA methylation profiling

Abstract

The present study aimed to identify novel methylation markers of clear cell renal cell carcinoma (ccRCC) using microarray methylation analysis and evaluate their prognostic relevance in patient samples. To identify cancer-specific methylated biomarkers, microarray profiling of ccRCC samples from our institute (n=12) and The Cancer Genome Atlas (TCGA) database (n=160) were utilized, and the prognostic relevance of candidate genes were investigated in another TCGA dataset (n=153). For validation, pyrosequencing analyses with ccRCC samples from our institute (n=164) and another (n=117) were performed and the potential clinical application of selected biomarkers was examined. We identified 22 CpG island loci that were commonly hypermethylated in ccRCC. Kaplan-Meier analysis of TCGA data indicated that only 4/22 loci were significantly associated with disease progression. In the internal validation set, Kaplan-Meier analysis revealed that hypermethylation of two loci, zinc finger protein 492 (ZNF492) and G protein-coupled receptor 149 (GPR149), was significantly associated with shorter time-to-progression. Multivariate Cox regression models revealed that hypermethylation of ZNF492 [hazard ratio (HR), 5.44; P=0.001] and GPR149 (HR, 7.07; P<0.001) may be independent predictors of tumor progression. Similarly, the methylation status of these two genes was significantly associated with poor outcomes in the independent external validation cohort. Collectively, the present study proposed that the novel methylation markers ZNF492 and GPR149 could be independent prognostic indicators in patients with ccRCC.

A Gene Signature of Survival Prediction for Kidney Renal Cell Carcinoma by Multi-Omic Data Analysis

“…In addition, DNA methylation is a major epigenetic modification that plays important roles in tumor development. Many genes (such as CRB3 [14], SFRP1 [15], ZNF492 , and GPR149 [16]) with an abnormal methylation status have been reported to be prognosis biomarkers for KIRC. Signatures formed by multiple genes with a changed methylation status have been reported to be powerful predictors of prognosis for hepatocellular carcinoma [17] and pancreatic cancer [18].…”

The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments

“…In recent years, several groups have used multi-omic data analysis to reveal groups of differentially methylated and expressed genes in surgically resected specimens of RCC or in the open data of ccRCC in TCGA (TCGA Research Network). The evidence generated confirms cluster analysis based on genomewide promoter methylation serves to identify panels of methylated genes associated to ccRCC disease progression [17,34,[72][73][74][75][76][77][78][79][80][81][82][83]. Some of these panels have been validated in an independent retrospective cohort and some have been incorporated into prognostic risk score models to enhance their prognostic biomarker effect [77,78].…”

“…Again, this panel has not yet been revalidated prospectively. Some of the panels focus mainly on two or more genes for prognostic classification of ccRCC patients [17,74,[81][82][83]. Other investigations evaluate tumor prognosis and progression based on analyzing the functional role of a particular gene and the likely mechanisms involved.…”

Clinical Significance of ADAMTS19, BMP7, SIM1, and SFRP1 Promoter Methylation in Renal Clear Cell Carcinoma

“…Since changes in the DNA methylation are often related to clinical-pathological parameters, 15 they might be useful to detect kidney cancer patients with more aggressive tumors and possibly poorer outcomes. Despite considerable efforts to identify novel DNA methylation biomarkers for the diagnosis and/or prognosis of renal cancer, [25][26][27][28][29] no marker has yet reached the clinic; therefore, further investigations are needed. The present study allowed us to identify frequent DNA methylation of ADAMTS19, BMP7, SIM1, and SFRP1 in ccRCCs, with 100% of specificity for the tumors.…”