Speaker: Professor Samra Turajlić, Cancer Research UK Manchester Institute Director
Title: Host-constrained evolution drives convergent tumour ecosystems in VHL-associated cancer
Abstract: Cancer evolves within a complex selective landscape, yet the extent to which this landscape is shaped by the host, and therefore predictable, remains unclear. Patients with von Hippel–Lindau (VHL) disease develop multiple clonally independent clear cell renal cell carcinomas within a shared germline and environmental context, providing a unique model to interrogate host-constrained evolution.
We analysed over 1,000 tumours from 112 patients with VHL disease, integrating genomic, single-nucleus RNA sequencing and spatial profiling. Following VHL loss as a founding event, tumours evolved along canonical genomic trajectories but showed little convergence within patients, consistent with stochastic acquisition of driver events. Rare instances of germline-imposed constraint were nonetheless apparent: patients with large germline VHL deletions encompassing the adjacent FANCD2 gene consistently inactivated VHL via somatic mutation or methylation rather than 3p loss, and germline variant severity further constrained the spectrum of acquired driver events.
Despite marked genetic divergence between tumours within the same individual, we observed striking convergence at both the malignant transcriptomic and microenvironmental level. Single-nucleus RNA sequencing revealed reproducible tumour and stromal cell states across independent tumours from the same patient, while spatial profiling demonstrated convergence of immune and stromal architecture. This convergence was only minimally explained by somatic genotype and clinical features, indicating substantial host-level constraint on tumour ecosystems.
Together, these findings reveal a hierarchical organisation of tumour evolution in which stochastic somatic events occur within rare germline-imposed constraints and converge upon a shared host-imposed cellular and ecological landscape.