The Genomic Landscape of Renal Oncocytomas

Oncocytomas are predominantly benign neoplasms possessing pathogenic mitochondrial mutations and accumulation of respiration-defective mitochondria, characteristics of unknown significance. Using exome and transcriptome sequencing we identified two main subtypes of renal oncocytoma. Type 1 is diploid with CCND1 rearrangements, whereas Type 2 is aneuploid (hypodiploid) with recurrent loss of chromosome 1, X or Y, and 14 and/or 21, which may represent a precursor to more aggressive eosinophilic chromophobe renal cell carcinoma (ChRCC). Oncocytomas activate 5'' adenosine monophosphate-activated protein kinase (AMP kinase) and Tp53 (p53), and display disruption of Golgi, and autophagy/lysosome defects, events attributed to defective mitochondrial function. Alleviation of this metabolic checkpoint in Type 2 by p53 mutations may allow progression to eosinophilic ChRCC, indicating that they represent higher risk.