Turajlic lab Cancer Dynamics Laboratory
: Testing evolutionary contingency in inherited renal cell cancer
Introduction
Pathogenic germline mutations in the von Hippel-Lindau (VHL) gene cause a high penetrance autosomal dominant tumour predisposition syndrome, VHL Disease.
Affected individuals develop multiple benign and/or malignant VHL deficient lesions across multiple tissue contexts including renal cysts and clear cell renal cell carcinomas (ccRCCs), central nervous system and retinal haemangioblastomas and neuroendocrine tumors such as pheochromocytoma.
These lesions demonstrate biallelic inactivation of VHL, however malignant transformation is observed in the kidney and less commonly the adrenal gland and pancreas, suggesting that the consequences of VHL inactivation are tissue-specific. Although VHL is widely expressed, organs such as the lungs and colon are unaffected by VHL disease suggesting that tumorigenesis is contingent on tissue-specific variation in gene expression or differing tumor microenvironment (TME) features.
In the VHL kidney, patients may develop many hundreds of renal cysts and tumours over their lifetime and management involves surveillance and surgery when the dominant lesion reaches 3cm in size. Profiling multiple independent tumours and cysts that have arisen in an identical germline and host environment presents a novel opportunity to infer the factors underlying cancer evolution and progression and extensive testing of evolutionary contigency.
Interrogate fundamental questions in evolutionary cancer biology providing experimental evidence for historical contingency (whether tumours arising in the context of the same germline background converge on similar trajectories) and a repeatable measure of how stochastic, deterministic forces and genetic drift contribute to tumour evolution.
Funding
Cancer Research UK, National Institutes of Health
Collaborators
W. M. Linehan (Urologic Oncology Branch, National Institute for Health), W. M. Drake (St Bartholomew’s Hospital, London).
