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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