The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis

Joshi, Shilpy; Tolkunov, Denis; Aviv, Hana; Hakimi, A. Ari; Yao, Ming; Hsieh, James J.; Ganesan, Shridar; Chan, Chang S.; White, Eileen

doi:10.1016/j.celrep.2015.10.059

Cited by 125 publications

(135 citation statements)

References 40 publications

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“…A recent comprehensive analysis of the mutational landscape of human renal oncocytomas revealed that there are two main subtypes (Joshi et al, 2015). Type 1 is characterized by CCND1 rearrangements whereas Type 2 is aneuploid with loss of chromosome 1, and X or Y and/or 14 and 21, and displays male gender bias.…”

Section: Oncocytomas Accumulate Defective Mitochondriamentioning

confidence: 99%

“…There are few and no recurrent somatic mutations in the nuclear genome in either subtype. Type 2 oncocytoma may be a precursor of the more aggressive eosinophilic chromophobe renal cell carcinoma (ChRCC) based on similar transcriptomes and copy number variations (Joshi et al, 2015). What both renal oncocytoma subtypes share in common is recurrent pathogenic mutations in the mitochondrial genome, which may lead to ROS production that could contribute oncogenic signaling or perhaps to accumulation of oncometabolites.…”

Section: Oncocytomas Accumulate Defective Mitochondriamentioning

confidence: 99%

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Mitochondria and Cancer

2016

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Decades ago Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events, which drive aberrant cancer cell proliferation, also alter biochemical metabolism including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy, provide building blocks for new cells, and control redox homeostasis, oncogenic signaling, innate immunity and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mitochondrial DNA limits tumorigenesis and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multi-functional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.

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Section: Oncocytomas Accumulate Defective Mitochondriamentioning

confidence: 99%

Section: Oncocytomas Accumulate Defective Mitochondriamentioning

confidence: 99%

Mitochondria and Cancer

2016

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“…Renal cell carcinoma (RCC) consists of morphologically, molecularly, and clinically distinct subtypes, including clear cell RCC (ccRCC, ~75%), papillary RCC (pRCC, ~15%), chromophobe RCC (chRCC, ~5%), unclassified RCC (uRCC, ~5%), and few extremely rare entities such as medullary RCC (mdRCC) and MiT-translocation RCC (tRCC) (<1% each) (1)(2)(3)(4)(5)(6)(7)(8)(9). ChRCC is relatively indolent despite its usual presentation as larger tumors (10), yet ~5%-10% of patients eventually develop metastases (11,12).…”

Section: Introductionmentioning

confidence: 99%

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

Casuscelli¹,

Weinhold²,

Gundem³

et al. 2017

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“…This suggests that autophagy promotes metabolic robustness and malignancy through maintenance of mitochondrial function and that autophagy inhibition may suppress Kras-driven lung cancers. Interestingly, human renal oncocytomas, which typically lack Ras mutations, have pathogenic mitochondrial genome mutations, respiration defects, energy stress, and defective autophagy and may owe their benign status to similar mechanisms found in Atg7-deficient Ras-driven tumors (Joshi et al 2015).…”

Section: Lung Cancermentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

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The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis

Cited by 125 publications

References 40 publications

Mitochondria and Cancer

Mitochondria and Cancer

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

Recent insights into the function of autophagy in cancer

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