The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis
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 diplo...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-12-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715012486 |
| _version_ | 1819161981692674048 |
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| author | Shilpy Joshi Denis Tolkunov Hana Aviv Abraham A. Hakimi Ming Yao James J. Hsieh Shridar Ganesan Chang S. Chan Eileen White |
| author_facet | Shilpy Joshi Denis Tolkunov Hana Aviv Abraham A. Hakimi Ming Yao James J. Hsieh Shridar Ganesan Chang S. Chan Eileen White |
| author_sort | Shilpy Joshi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T17:20:59Z |
| format | Article |
| id | doaj.art-24830e8cfa6640219c7cdce05fcd3e09 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T17:20:59Z |
| publishDate | 2015-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-24830e8cfa6640219c7cdce05fcd3e092022-12-21T18:18:49ZengElsevierCell Reports2211-12472015-12-011391895190810.1016/j.celrep.2015.10.059The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to TumorigenesisShilpy Joshi0Denis Tolkunov1Hana Aviv2Abraham A. Hakimi3Ming Yao4James J. Hsieh5Shridar Ganesan6Chang S. Chan7Eileen White8Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USARutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USADepartment of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, One Robert Wood Johnson Place, MEB 212, New Brunswick, NJ 08901, USAUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USARutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USAHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USARutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USARutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USARutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USAOncocytomas 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.http://www.sciencedirect.com/science/article/pii/S2211124715012486oncocytomacancer metabolismmitochondriacancer genomicslysosome |
| spellingShingle | Shilpy Joshi Denis Tolkunov Hana Aviv Abraham A. Hakimi Ming Yao James J. Hsieh Shridar Ganesan Chang S. Chan Eileen White The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis Cell Reports oncocytoma cancer metabolism mitochondria cancer genomics lysosome |
| title | The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis |
| title_full | The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis |
| title_fullStr | The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis |
| title_full_unstemmed | The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis |
| title_short | The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis |
| title_sort | genomic landscape of renal oncocytoma identifies a metabolic barrier to tumorigenesis |
| topic | oncocytoma cancer metabolism mitochondria cancer genomics lysosome |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715012486 |
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