Metabolomics informs common patterns of molecular dysfunction across histologies of renal cell carcinoma.

The last 30 years of research in renal cell carcinoma (RCC) has revealed that the vast majority of RCC histologies share a recurrent pattern of mutations to metabolic genes, including VHL, MTOR, ELOC, TSC1/2, FH, SDH, and mitochondrial DNA. This has prompted intense study of the consequences of these mutations on cellular metabolism and physiology in vivo by leveraging high-throughput technologies to measure small-molecule metabolites (i.e., metabolomics). The purpose of this review is to give a broad and integrated view on the discoveries made in RCC with metabolomics, and to give a basic understanding of the experimental design of metabolomic studies. Our discussion is organized around five concepts which synthesize discoveries from genomics and metabolomics into the molecular basis of RCC and transcend the different RCC histologies: (1) metabolic phenotypes unique to certain genotypes, (2) mitochondrial dysfunction, (3) the oxidative stress response, (4) epigenetics, and (5) therapy targeted to metabolism. We conclude by proposing several promising lines of investigation that intersect metabolism with emerging ideas in RCC biology.