Methylation Signature for Prediction of Progression Free Survival in Surgically Treated Clear Cell Renal Cell Carcinoma

Abstract

Background Little is known about epigenetic silencing of genes by promoter hypermethylation in renal cell carcinoma (RCC). The aim of this study was to identify prognostic methylation markers in surgically treated clear cell RCC (ccRCC). Methods Methylation patterns were assayed using the Infinium HumanMethylation450 BeadChip array on pairs of ccRCC and normal tissue from 12 patients. Using quantitative PSQ analysis, tumor-specific hypermethylated genes were validated in 25 independent cohorts and their clinical relevance was also verified in 152 independent cohorts. Results Using genome-wide methylation array, Zinc finger protein 278 ( ZNF278 ), Family with sequence similarity 155 member A ( FAM155A ) and Dipeptidyl peptidase 6 ( DPP6 ) were selected for tumor-specific hypermethylated genes in primary ccRCC. The promoter methylation of these genes occurred more frequently in ccRCC than normal kidney in independent validation cohort. The hypermethylation of three genes were associated with advanced tumor stage and high grade tumor in ccRCC. During median follow-up of 39.2 (interquartile range, 15.4–79.1) months, 22 (14.5%) patients experienced distant metastasis. Multivariate analysis identified the methylation status of these three genes, either alone, or in a combined risk score as an independent predictor of distant metastasis. Conclusion The promoter methylation of ZNF278 , FAM155A and DPP6 genes are associated with aggressive tumor phenotype and early development of distant metastasis in patients with surgically treated ccRCC. These potential methylation markers, either alone, or in combination, could provide novel targets for development of individualized therapeutic and prevention regimens.

Identification of Dipeptidyl Peptidase (DPP) Family Genes in Clinical Breast Cancer Patients via an Integrated Bioinformatics Approach

“…Therefore, DPP4 may be regulated by post-translational modifications (PTMs) or epigenetic-related mechanisms [ 51 , 52 ]. DPP6 served as a tumor-specific hypermethylated gene [ 53 ] and was significantly related to the prognosis of clear cell renal cell carcinoma patients [ 54 ]. Our data showed that DPP6 had low expression levels in breast cancer tissues at both the transcription and protein levels, and was further related to good prognoses in breast cancer patients, which also suggested that DPP6 may act as a tumor suppressor in cancer development.…”

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.…”

DNA Methylation-Based Panel Predicts Survival of Patients With Clear Cell Renal Cell Carcinoma and Its Correlations With Genomic Metrics and Tumor Immune Cell Infiltration

“…Pan et al (2019) introduced a 5-gene signature including OTX1, MATN4, PI3, ERVV-2, and NFE4 that was associated with the progression and prognosis of ccRCC patients. Kang et al (2019) identified a 3-CpG site based promoter methylation signature associated with aggressive tumor phenotype and progression free survival in patients with ccRCC after surgical treatment. Zeng et al (2019) indicated that the combination of IDUA, NDST1, SAP30L, CRYBA4, and SI was a prognostic signature (5-gene signature) in ccRCC.…”