Deciphering Clonal Evolution in Hereditary Renal Cell Carcinomas

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1 Background: An improved understanding of the factors that drive cancer growth and progression is 2 fundamental for improving outcomes in patients with cancer. Individuals with Von Hippel-Lindau (VHL) 3 disease develop multiple vascular tumours in their lifetime including many hundreds of malignant 4 cysts and clear cell renal cell carcinoma (ccRCCs). These tumours are the genomic mirror image of 5 sporadic ccRCCs and display variable clinical phenotypes. Profiling multiple, independent tumours 6 that have arisen in an identical germline and host environment offers an intrinsically controlled model 7 to study the factors underlying cancer evolution and progression in general. We will leverage the 8 unique clinical cohort of patients with VHL Disease at the Clinical Centre to study how the molecular 9 landscape (Objective 1), the tumour microenvironment (TME) (Objective 2) and the metabolome 10 (Objective 3) promote or restrain cancer growth. 11 Methods: Subjects will be recruited to this prospective cohort study from the Urology Oncology 12 Branch at the National Cancer Institute. Growth kinetics of individual tumours will be tracked 13 radiologically. During procurement, tumours are identified and correlated with imaging. We will 14 perform multiparametric molecular profiling, integrating all datasets to achieve our study objectives. 15 Using next generation sequencing we will characterise the events that underlie malignant 16 transformation (Objective 1.1) and the molecular events associated with differential growth kinetics 17 (Objective 1.1). We will explore events associated with tumour fromation in extra-renal sites 18 (Objective 1.3) and how molecular/environmental variants influence variable phenotypic penetration 19 amongst VHL kindred (Objective 1.4). To assess the role of the TME, we will use genomic profiling to 20 assess the neoantigen landscape (Objective 2.1) and identify differential immune cell lineages using 21 RNA sequencing (Objective 2.2). We will validate these fidnings with multiplex immunohistochemistry 22 (IHC) approach. We will assess the perturbed metabolome utilising transcriptome profiling (Objective 23 3.1) and conduct a pilot study to assess genomic and transcriptomic changes with stable isotope- 24 resolved metabolic profiles obtained from VHL tumor tissue obtained intraoperatively. 25 Conclusion: This will be the most comprehensive molecular profiling of cancers arising in VHL 26 disease. It has the potential to address key questions regarding evolutionary cancer biology and to 27 identify the triggers for tumour growth and progression and hence predictive or prognostic biomarkers 28 which may have a wider relevance to cancer. It may inform novel therapeutic strategies for the 29 treatment and prevention of hereditary and sporadic ccRCC.