Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal
- Author(s)
- Fernández-Sanromán, Á; Fendler, A; Tan, BJY; Cattin, AL; Spencer, C; Thompson, R; Au, L; Lobon, I; Pallikonda, HA; Martin, A; Byrne, F; Franz, A; Mikolajczak, A; Rahman, H; Tippu, Z; Shepherd, STC; Feng, H; Deng, D; Rowan, A; Pickering, L; Furness, AJS; Young, K; Nicol, D; Rudman, SM; O'Brien, T; Edmonds, K; Chandra, A; Hazell, S; Litchfield, K; Kassiotis, G; Larkin, J; Turajlic, S;
- Journal Title
- Cancer Discovery
- Publication Type
- Online publication before print
- 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.
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1158/2159-8290.Cd-24-0499
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-01-21 12:22:25
Last Modified: 2025-01-21 12:27:30