Cancer cells display complex genomic aberrations that include large-scale genetic rearrangements and epigenetic modulation that are not easily captured by short-read sequencing. This study presents a novel approach for simultaneous profiling of long-range genetic and epigenetic changes in matched cancer samples, focusing on clear cell renal cell carcinoma (ccRCC). ccRCC is a common kidney cancer subtype frequently characterized by a 3p deletion and the inactivation of the von Hippel-Lindau (VHL) gene. We performed integrated genetic, cytogenetic, and epigenetic analyses on paired tumor and adjacent nontumorous tissue samples. Optical genome mapping identified genomic aberrations as structural and copy number variations, complementing exome-sequencing findings. Single-molecule methylome and hydroxymethylome mapping revealed a significant global reduction in 5hmC level in both sample pairs, and a correlation between both epigenetic signals and gene expression was observed. The single-molecule epigenetic analysis identified numerous differentially modified regions, some implicated in ccRCC pathogenesis, including the genes VHL, PRCC, and PBRM1. Notably, pathways related to metabolism and cancer development were significantly enriched among these differential regions. This study demonstrates the feasibility of integrating optical genome and epigenome mapping for comprehensive characterization of matched tumor and adjacent tissue, uncovering both established and novel somatic aberrations.

• MeSH
• Epigenesis, Genetic MeSH
• Epigenome * MeSH
• Epigenomics methods   MeSH
• Genome, Human MeSH
• Carcinoma, Renal Cell * genetics   pathology   MeSH
• Humans MeSH
• Chromosome Mapping * methods   MeSH
• DNA Methylation MeSH
• Von Hippel-Lindau Tumor Suppressor Protein genetics   MeSH
• Kidney Neoplasms * genetics   pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• DNA Copy Number Variations MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Von Hippel-Lindau Tumor Suppressor Protein MeSH
• VHL protein, human MeSH Browser