Deciphering evolutionary trajectories in hereditary renal cell carcinomas

Abstract

Establishing the limits of predictability in cancer evolution has significant implications for precision medicine. Clear cell renal cell carcinoma (ccRCC) follows highly deterministic evolutionary pattern with conserved order of mutation and copy number events and mutual exclusivity. While the repeatability of evolutionary trajectories within individuals cannot be determined in those with sporadic cancers, individuals with a hereditary predisposition may develop dozens of tumours over the course of their lifetime offering a unique opportunity to infer the factors associated with progression. I present novel insights into the evolution of ccRCC on the constrained background of germline von Hippel-Lindau (VHL) mutation through molecular analysis of 1321 VHLrelated neoplasms from 132 patients. By integrating panel sequencing, single nucleus RNA sequencing, and detailed clinicopathological data, I uncover novel findings related to genotype/phenotype correlations, the interplay of evolutionary contingency and convergence, and the constraints active in the evolution of VHL related neoplasms. The study demonstrates that chance plays a predominant role in ccRCC evolution, within the constraints of available evolutionary paths, as clonally independent ccRCCs with germline VHL mutations exhibit random somatic profiles across the cohort. However, specific examples of evolutionary convergence are also observed. Novel routes to biallelic inactivation of VHL in transformed tumours are identified, and a subset of tumours without VHL loss suggests alternative evolutionary paths that may represent evolutionary ‘deadends’. Moreover, the study highlights the influential role of the cell-of-origin lineage in shaping the selection of somatic events. I refine the understanding of genotype-phenotype correlations in VHL disease showing that tumours retaining some regulation of hypoxia inducible factor (HIF) exhibit distinct molecular profiles. The enrichment of chromosomal instability and high-risk chromosomal loci in larger renal tumours reconciles the association between metastasis risk and tumor diameter in VHL disease. Lastly, in the context of the SARS-CoV-2 pandemic, I report the establishment of a prospective, pan-cancer study (CAPTURE) focused on longitudinal immune profiling of cancer patients and their response to COVID-19 vaccination.