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.
authors.affiliation: Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: Shilpy
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Tolkunov
authors.affiliation: Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, One Robert Wood Johnson Place, MEB 212, New Brunswick, NJ 08901, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: Aviv
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Abraham A
authors.initials: AA
authors.lastname: Hakimi
authors.affiliation: Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
authors.affiliation: Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA.
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA. Electronic address: chanc3@cinj.rutgers.edu.
authors.forename: Chang S
authors.initials: CS
authors.lastname: Chan
authors.affiliation: Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Molecular Biology and Biochemistry, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA. Electronic address: epwhite@cinj.rutgers.edu.
authors.forename: Eileen
authors.initials: E
authors.lastname: White
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018249:Adenoma, Oxyphilic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002403:Cathepsins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D059785:Karyotype; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D055372:AMP-Activated Protein Kinases; D002403:Cathepsins; D019938:Cyclin D1; D051907:Lysosomal Membrane Proteins; D008687:Metformin; D016159:Tumor Suppressor Protein p53; C530104:CCND1 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1
keywords: cancer genomics; cancer metabolism; lysosome; mitochondria; oncocytoma