The genomic landscape of renal oncocytoma identifies a metabolic barrier to tumorigenesis Journal Article


Authors: Joshi, S.; Tolkunov, D.; Aviv, H.; Hakimi, A. A.; Yao, M.; Hsieh, J. J.; Ganesan, S.; Chan, C. S.; White, E.
Article Title: The genomic landscape of renal oncocytoma identifies a metabolic barrier to tumorigenesis
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.
Keywords: autophagy; homeostasis; cell carcinoma; cancer-cells; complex-i; lung-tumors; mitochondrial-dna mutations; biguanides; lamp-2
Journal Title: Cell Reports
Volume: 13
Issue: 9
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2015-12-01
Start Page: 1895
End Page: 1908
Language: English
ACCESSION: WOS:000366047000016
DOI: 10.1016/j.celrep.2015.10.059
PROVIDER: wos
PUBMED: 26655904
PMCID: PMC4779191
Notes: Article -- Source: Wos
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  1. James J Hsieh
    125 Hsieh
  2. Abraham Ari Hakimi
    324 Hakimi