AbstractRenal cell carcinoma (RCC) comprises several histological types characterised by different genomic and epigenomic aberrations; however, the molecular pathogenesis of each type still requires further exploration. We perform whole-genome sequencing of 128 Japanese RCC cases of different histology to elucidate the significant somatic alterations and mutagenesis processes. We also perform transcriptomic and epigenomic sequencing to identify distinguishing features, including assay for transposase-accessible chromatin sequencing (ATAC-seq) and methyl sequencing. Genomic analysis reveals that the mutational signature differs among the histological types, suggesting that different carcinogenic factors drive each histology. From the ATAC-seq results, master transcription factors are identified for each histology. Furthermore, clear cell RCC is classified into three epi-subtypes, one of which expresses highly immune checkpoint molecules with frequent loss of chromosome 14q. These genomic and epigenomic features may lead to the development of effective therapeutic strategies for RCC.