The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis
Shilpy Joshi,
Denis Tolkunov,
Hana Aviv,
Abraham A. Hakimi,
Ming Yao,
James J. Hsieh,
Shridar Ganesan,
Chang S. Chan,
Eileen White
Affiliations
Shilpy Joshi
Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA
Denis Tolkunov
Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA
Hana Aviv
Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, One Robert Wood Johnson Place, MEB 212, New Brunswick, NJ 08901, USA
Abraham A. Hakimi
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
Ming Yao
Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA
James J. Hsieh
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
Shridar Ganesan
Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA
Chang S. Chan
Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA
Eileen White
Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA
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 with recurrent loss of chromosome 1, X or Y, and/or 14 and 21, which may proceed to more aggressive eosinophilic chromophobe renal cell carcinoma (ChRCC). Oncocytomas activate 5′ adenosine monophosphate-activated protein kinase (AMPK) and Tp53 (p53) and display disruption of Golgi and autophagy/lysosome trafficking, events attributed to defective mitochondrial function. This suggests that the genetic defects in mitochondria activate a metabolic checkpoint, producing autophagy impairment and mitochondrial accumulation that limit tumor progression, revealing a novel tumor-suppressive mechanism for mitochondrial inhibition with metformin. Alleviation of this metabolic checkpoint in type 2 by p53 mutations may allow progression to eosinophilic ChRCC, indicating that they represent higher risk.
