Investigating the molecular underpinnings of clear cell renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) is the most common type of kidney cancer and among the top ten cancers by incidence. Clear cell RCC (ccRCC) is the most frequent histological subtype of RCC, accounting for 75% of RCC diagnoses. Nearly one-fifth of ccRCC patients are diagnosed with advanced or metastatic disease and are ineligible for surgery. In patients with earlier stage disease, surgery is a first line treatment option; yet, one-third eventually recur with advanced stage disease. The treatment paradigm for advanced stage ccRCC consists of immune checkpoint blockade (ICB), a type of immunotherapy (IO), and targeted therapy, including anti-angiogenic agents. However, only 13% of advanced stage ccRCC patients have a life expectancy longer than 5 years, highlighting the acute need to better understand the genetic and genomic characteristics of ccRCC with the ultimate goal of improving clinical outcomes. Genomically, ccRCC is characterized by somatic loss of chromosome 3p and inactivation of the VHL tumor suppressor. In addition, somatic mutations in epigenetic modulators including PBRM1, SETD2, BAP1 and KDM5C, are common events in ccRCC. PBRM1 mutations are associated with clinical benefit to IO in patients who have been previously treated with receptor tyrosine kinase inhibitors (RTKi), while BAP1 mutations are associated with poor prognosis. However, little is known about alterations occurring at lower frequencies and whether they are associated with clinical outcomes. In addition to distinct somatic alterations, ccRCC exhibits aberrant expression of endogenous retroviruses (ERVs), a type of transposable element (TE). TEs, which are mobile repetitive genomic elements and comprise nearly half of the human genome, are typically silenced in healthy adult human tissues through epigenetic mechanisms. Distinct ERVs have been detected in ccRCC and expression of a select few may associate with improved clinical outcomes in advanced stage patients. Yet, a systematic evaluation of TE expression and their relevance to clinical outcomes in ccRCC has not been undertaken. To comprehensively characterize the genomic landscape and TE expression in ccRCC, we utilized publicly available Whole Exome Sequencing (WES) and RNA-sequencing (RNAseq) datasets of ccRCC clinical cohorts and cell lines. We employed computational tools and techniques to call somatic variants, in addition to quantifying TE expression. We determined that ERVs are more commonly differentially expressed across the major epigenetic mutational subtypes in ccRCC compared to other TE types, and expression of distinct ERVs associated with improved clinical outcomes in conjunction with specific somatic alterations. Beyond the most frequent somatic alterations, we additionally showed that a larger proportion of genes and copy number alterations occur at lower frequencies in ccRCC. Importantly, select low frequency alterations defined genomic subsets of patients who may experience improved benefit or resistance to the standard of care therapies. Overall, this dissertation broadens our understanding of ccRCC biology and enables potential precision medicine approaches in this cancer type.