Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Abstract

SummaryThe evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

“…Studies have shown that VHL inactivation alone is insufficient for tumorigenesis, highlighting the importance of the SCNA and secondary driver genes for formation and progression of ccRCC. Turajlic et al . further demonstrate the importance of these elements for the evolution of ccRCC.…”

“…The ‘PBRM1 → SETD2’ subtype was defined by mutatons in PBRM1 followed by SETD2 , the ‘PBRM1 → PI3k’ subgroup was defined by PBRM1 mutations followed by alterations in the PI3K/AKT pathway, e.g. TSC1 and mTOR, the ‘PBRM1 → SCNA’ subgroup was defined by mutations in PBRM1 followed by a driver SCNA event, the ‘BAP1 driven’ subgroup was defined by BAP1 as the single driver event with VHL , and finally the ‘multiple clonal drivers’ evolutionary subtype, which was defined by tumours in which two or more secondary driver genes where clonally mutated …”

“…Although TCEB1 inactivation is able to account for a fraction of wt VHL ccRCC they are extremely rare, with approximately 12 cases reported worldwide . Vitally, these do not account for all wt VHL ccRCC cases, still leaving the root cause for many wt VHL ccRCC cases unknown.…”

“…Vitally, these do not account for all wt VHL ccRCC cases, still leaving the root cause for many wt VHL ccRCC cases unknown. Referring back to the seven evolutionary subtypes of ccRCC identified by Turajlic et al ., one of the identified evolutionary trajectories was ‘ VHL wild‐type’. Cases within this group were defined by active VHL within their tumours, i.e.…”

Updates on mechanistic insights and targeting of tumour metastasis

“…Olimab, a human IgG1 antibody that binds to platelet-derived growth factor receptor α (PDGFR-α), is a new drug for soft tissue sarcomas. Recently, through the analysis of multiple clear cell renal cell carcinoma (ccRCC) cases, the evolutionary potential of MMP is proposed as a biomarker for intervention and detection 78. In recent years, new targets are adopted at a rapid and exponential rate, following by new tumour-targeting drugs.…”