Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma

On the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences between clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with chromatin modifier genes or TFE3 gene fusion were present within specific subtypes as well as spanning multiple subtypes. Differences in patient survival and in alteration of specific pathways—including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR—could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.