Tracking nongenetic evolution from primary to metastatic ccRCC: TRACERx Renal
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Angel Fernández Sanromán Annika Fendler Benjy JY Tan Anne-Laure Cattin Charlotte Spencer Rachael Thompson Lewis Au Irene Lobon Husayn Pallikonda Alice Martin Fiona Byrne Antonia Franz Anna Mikolajczak Haseeb Rahman Zayd Tippu Scott Shepherd Geoffrey Feng Daqi Deng Andrew Rowan Lisa Pickering Andrew JS Furness Kate Young David Nicol Sarah Maria Rudman Tim O'Brien

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Abstract

While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve 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 non-genetic 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 co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor 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 non-genetic evolution patterns in ccRCC.