Dissecting Convergent Somatic and Germline Alterations that Mediate the Origins and Evolution of Kidney Cancer - Germline pathogenic mutations (e.g. VHL, BAP1) and common variants are linked to the development of clear cell renal cell carcinoma (ccRCC), and recurrent somatic alterations are linked to ccRCC pathogenesis and clinical states. In certain cases, exemplified by germline and somatic mutations in VHL, direct somatic-germline interactions mediate ccRCC pathogenesis. However, deciphering the processes that underlie multifaceted germline and somatic events in ccRCC remains a major challenge, particularly given the expanding scope of recently nominated germline and somatic noncoding regulatory mutations and structural variants in ccRCC genomes. Furthermore, while ccRCC molecular and histopathologic heterogeneity may influence clinical states, how somatic-germline interactions promote spatial heterogeneity in ccRCC are largely unknown. Finally, given the rapidly expanding types of molecular events in known ccRCC and actionable genes, specifically including germline and somatic structural variants, new approaches are needed to jointly understand and consider these features in a precision oncology framework. Hypothesis-driven consideration of somatic-germline interactions, paired with emerging computational and functional approaches, may inform how germline and somatic events biologically connect to promote ccRCC pathogenesis, unique histopathologic states, and distinct clinical outcomes. The overarching hypothesis of this project is that biologically convergent germline-somatic coding and regulatory events mediate ccRCC pathogenesis, and that these properties shape spatial histopathologic patterns and subsequent clinical states. We will evaluate this hypothesis through the following independent and hypothesis-driven Specific Aims: 1) Determine the integrated germline and somatic regulatory events that contribute to ccRCC oncogenesis; 2) Define the somatic-germline interactions that influence spatial heterogeneity in ccRCC; and 3) Dissect the clinical actionability of germline and somatic structural variants in ccRCC. Taken together, this hypothesis-driven proposal will define the relationship between specific somatic-germline interactions and properties that promote oncogenesis, spatial histopathologic patterns, and clinical actionability in ccRCC using a novel suite of computational, functional, and cross-disciplinary approaches. Broadly, this project will provide an integrative genomic, histopathologic, and experimental framework for understanding clinically and biologically relevant somatic-germline molecular underpinnings across tumor types.
