Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal

Area of Science:

• Oncology
• Genetics
• Immunology

Background:

• Genetic evolution in clear cell renal-cell carcinoma (ccRCC) and its clinical impact are known.
• The co-evolution of genetic features with phenotype and tumor microenvironment (TME) in ccRCC is not well understood.

Purpose of the Study:

• To investigate the interplay between genetic alterations, phenotypic changes, and the TME in ccRCC.
• To identify non-genetic mechanisms driving tumor evolution in ccRCC.

Main Methods:

• Joint genomic and transcriptomic analysis of 243 ccRCC samples from 79 patients in the TRACERx Renal study.
• Phylogenetic analysis and integration of tumor transcriptomes to study evolutionary patterns.

Main Results:

• Over 40% of intratumor heterogeneity in ccRCC is not explained by genetic alterations.
• Convergent evolution of phenotypic traits like proliferation and metabolic reprogramming was observed, linked to aneuploidy.
• A shift in the TME from anti-tumor to immunosuppressive was identified, associated with late-acquirable ccRCC drivers (9p loss, SETD2 mutations).
• Co-evolution between the tumor and T cell repertoire was uncovered.

Conclusions:

• Non-genetic factors play a substantial role in ccRCC evolution, contributing significantly to intratumor heterogeneity.
• Understanding these non-genetic evolution patterns is crucial for developing effective ccRCC therapies.