Clear cell renal cell carcinoma ontogeny and mechanisms of lethality

The molecular features that define clear cell renal cell carcinoma (ccRCC) initiation and progression are being increasingly defined. The TRACERx Renal studies and others that have described the interaction between tumour genomics and remodelling of the tumour microenvironment provide important new insights into the molecular drivers underlying ccRCC ontogeny and progression. Our understanding of common genomic and chromosomal copy number abnormalities in ccRCC, including chromosome 3p loss, provides a mechanistic framework with which to organize these abnormalities into those that drive tumour initiation events, those that drive tumour progression and those that confer lethality. Truncal mutations in ccRCC, including those in VHL , SET2 , PBRM1 and BAP1 , may engender genomic instability and promote defects in DNA repair pathways. The molecular features that arise from these defects enable categorization of ccRCC into clinically and therapeutically relevant subtypes. Consideration of the interaction of these subtypes with the tumour microenvironment reveals that specific mutations seem to modulate immune cell populations in ccRCC tumours. These findings present opportunities for disease prevention, early detection, prognostication and treatment. The molecular features that define the initiation and progression of clear cell renal cell carcinoma (ccRCC) are being increasingly defined. This Review summarizes common genomic and chromosomal copy number abnormalities in ccRCC, providing a mechanistic framework with which to organize these features into initiating events, drivers of progression and factors that confer lethality. Key points Chromosome 3p loss is an almost universal finding in both hereditary and sporadic clear cell renal cell carcinoma (ccRCC). The near ubiquitous loss of a second copy of VHL seems to provide a selective advantage for cells, as well as leading to defects in DNA repair and an increase in genomic instability. Secondarily mutated genes in ccRCC, including PBRM1 , SETD2 and BAP1 , as well as copy number changes in chromosomes 9p and 14q, are associated with prognostically important molecular and phenotypic characteristics that can be used to classify tumours into subgroups. Tumour genomic features are associated with distinct immune phenotypes; for example, PBRM1 mutations are associated with reduced infiltration of T cells. Efforts are underway to link genomic features to specific therapeutic strategies for patients with ccRCC.