Dissecting Convergent Somatic and Germline Alterations that Mediate the Origins and Evolution of Kidney Cancer

PROJECT SUMMARY Germline pathogenic mutations and common variants have been implicated in the development of clear cell renal cell carcinoma (ccRCC). Similarly, recurrent somatic alterations are key to ccRCC pathogenesis and distinct clinical states. Combinations of germline and somatic mutations can directly interact to disrupt the same

gene in ccRCC, traditionally exemplified by biallelic pathogenic coding mutations in VHL. Novel combinations of different genes and alteration types in germline and somatic genomes may also contribute to pathogenesis and clinical states (“convergence”); however, studying these relationships remains a major challenge for the cancer

genetics field. For example, the expanding scope of germline and somatic events in noncoding regions, most of which have uncertain functional impact, significantly complicates discovery of genes that dysregulate convergent biological processes. Additionally, whether related germline and somatic events promote tumor heterogeneity,

which may also impact clinical outcomes, is largely unknown and historically difficult to study given the lack of appropriate methodologies and cohorts. Finally, certain germline and somatic alteration types (e.g. structural variants) remain poorly understood in ccRCC, but determination of their impact on actionable genes is necessary

to maximize precision oncology approaches. Our team has developed strategies to overcome these significant challenges, and our subsequent preliminary findings indicate that ccRCC exhibits previously unappreciated forms of convergence. These include combinations of germline and somatic events that: (i) alter transcriptional

states of biologically related genes through noncoding variation; (ii) impact chromatin regulatory complexes to result in clinically relevant histologic heterogeneity; and (iii) indirectly disrupt actionable genes through novel structural mechanisms. Broadly, hypothesis-driven investigations of these unconventional germline and somatic

relationships may inform how they promote ccRCC pathogenesis, unique histopathologic states, and distinct clinical outcomes. Building on our extensive preliminary data and longstanding expertise in computational and functional cancer genomics, the overarching hypothesis of this project is that novel biologically convergent

germline and somatic alterations contribute to ccRCC pathogenesis, and these convergent properties jointly shape tumor heterogeneity and clinical states. We will evaluate this hypothesis through the following independent Specific Aims: 1) Determine the convergent germline and somatic noncoding events that contribute to

oncogenesis; 2) Define the germline and somatic alterations that jointly influence clinically relevant spatial heterogeneity; and 3) Dissect the clinical actionability of germline and somatic structural variants in inclusive cohorts. This hypothesis-driven proposal will reveal relationships between germline and somatic events, tumor

heterogeneity, and clinical actionability in ccRCC via a suite of innovative cross-disciplinary approaches. Overall, this proposal will enable a new understanding of how germline and somatic genomes jointly shape tumor initiation and evolution in ccRCC, and potentially across cancers.