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

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1895-1908
Number of pages14
JournalCell Reports
Volume13
Issue number9
DOIs
StatePublished - Dec 1 2015

Keywords

  • Cancer genomics
  • Cancer metabolism
  • Lysosome
  • Mitochondria
  • Oncocytoma

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