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.