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The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis
- Source :
- Cell Reports, Vol 13, Iss 9, Pp 1895-1908 (2015)
- Publication Year :
- 2015
- Publisher :
- Elsevier, 2015.
-
Abstract
- SummaryOncocytomas 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.
- Subjects :
- Male
DNA Copy Number Variations
Chromophobe Renal Cell Carcinoma
Karyotype
Golgi Apparatus
cancer metabolism
Mitochondrion
Biology
AMP-Activated Protein Kinases
Kidney
General Biochemistry, Genetics and Molecular Biology
Transcriptome
medicine
Autophagy
Adenoma, Oxyphilic
Humans
Oncocytoma
Cyclin D1
Renal oncocytoma
Exome
Carcinoma, Renal Cell
lcsh:QH301-705.5
cancer genomics
Sequence Analysis, RNA
Lysosome-Associated Membrane Glycoproteins
oncocytoma
medicine.disease
Cathepsins
Kidney Neoplasms
Metformin
3. Good health
Cell biology
mitochondria
Cell Transformation, Neoplastic
lcsh:Biology (General)
Tumor progression
lysosome
Female
Tumor Suppressor Protein p53
Lysosomes
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 13
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....229bf0eaecd6ef77a147623dcbebefee