The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis Academic Article uri icon

Overview

MeSH Major

  • Adenoma, Oxyphilic
  • Cell Transformation, Neoplastic
  • Kidney Neoplasms

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.

publication date

  • December 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4779191

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2015.10.059

PubMed ID

  • 26655904

Additional Document Info

start page

  • 1895

end page

  • 908

volume

  • 13

number

  • 9