Abstract

Abstract Although the key aspects of genetic evolution and their clinical implications in clear-cell renal cell carcinoma (ccRCC) are well documented, how genetic features coevolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic–transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive nongenetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming, and overexpression of putative cGAS–STING repressors amid high aneuploidy. We also uncover a coevolution between the tumor and the T-cell repertoire, as well as a longitudinal shift in the TME from an antitumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically relevant and hitherto underappreciated nongenetic evolution patterns in ccRCC. Significance: Using joint genomic–transcriptomic analysis of 243 samples, we reveal recurrent patterns of nongenetic evolution in ccRCC not exclusively governed by genetic factors, including T-cell depletion, tumor T-cell receptor coevolution, potential cGAS–STING repression, and increased cell proliferation. These patterns can aid clinical management and guide novel treatment approaches.