Epigenomic subtypes and prognostic methylation signatures in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is characterized by marked epigenetic dysregulation, contributing to aberrant gene expression and tumor progression. To expand current knowledge on genome-wide methylation patterns in ccRCC, we performed Methylated DNA Immunoprecipitation sequencing (MeDIP-seq) on tumor samples from 116 ccRCC patients and 34 adjacent normal renal tissues. We identified differentially methylated regions (DMRs) and integrated these findings with genome-wide copy number alterations.

ccRCC tumors exhibited global hypomethylation combined with focal hypermethylation, particularly within intergenic and repetitive genomic regions. Unsupervised clustering revealed three distinct subtypes, including one subtype characterized by chromosomal instability, synchronous metastasis, and poor survival outcomes. We developed a novel methylation score (MethScore), based on hypermethylated regions, which strongly correlated with disease stage and independently predicted overall survival beyond age and clinical stage. Notably, high methylation levels of specific DMRs were linked to recurrence and advanced disease. Validation with TCGA Kidney Renal Clear Cell Carcinoma methylation data supported the prognostic value of these hypermethylated regions. Additionally, MeDIP-seq accurately detected critical copy number alterations, particularly chromosome 3p loss, which were found in 88% of tumors.

Together, our findings demonstrate that genome-wide methylation profiling can resolve clinically relevant ccRCC subtypes, uncover novel biomarkers of disease aggressiveness, and improve patient risk stratification beyond current clinical models.