A family case with germline<i>TSC1</i>and mtDNA mutations developing bilateral eosinophilic chromophobe renal cell carcinomas without other typical phenotype of tuberous sclerosis

Sakamoto, Hiromasa; Yamasaki, Toshinari; Sumiyoshi, Takayuki; Utsunomiya, Noriaki; Takeda, Masatoshi; Kamba, Tomomi; Nakamura, Eijiro; Ogawa, Osamu

doi:10.1136/jclinpath-2018-205211

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…Thus, SOD1 is a part of a neuronal nutrient-sensing machinery that is based on tau and mTORC1, and functionally connects extracellular cues to mitochondrial functioning, enabling nutrients to sustain OXPHOS and prevent unwanted mtDNA synthesis. It is possible that disruption of NiMA contributes to oxidative damage and propagation of mtDNA mutations linked to diseases such as AD ( Blanchard et al, 1993 ; Carrieri et al, 2001 ; Chagnon et al, 1999 ; Chen et al, 2016 ; Corral-Debrinski et al, 1994 ; Coskun et al, 2004 ; Hudson et al, 2012 ; Inczedy-Farkas et al, 2014 ; Lakatos et al, 2010 ; Van Der Walt et al, 2004 ), ALS ( Wiedemann et al, 2002 ) and TS ( Sakamoto et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers

Norambuena¹,

Sun²,

Wallrabe³

et al. 2022

Neurobiology of Disease

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Section: Introductionmentioning

confidence: 99%

SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers

Norambuena¹,

Sun²,

Wallrabe³

et al. 2022

Neurobiology of Disease

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“…Variants were called using SAMtools version 1.2 and BCFtools version 1.2 (http://www.htslib.org/), and were annotated by SnpEff version 4.1 (http://snpeff.sourceforge.net/index.html/). 23 Variants with a coverage greater than ×10 and with a Phred quality score greater than 20 were filtered. Variants assigned to the single nucleotide polymorphism database, those that were synonymous, and intron variations were filtered out.…”

Section: Methodsmentioning

confidence: 99%

Functional and genomic characterization of patient‐derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma

et al. 2020

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Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient‐derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole‐exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus‐resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein 9‐mediated heterozygous knockdown of DNMT1 in the temsirolimus‐sensitive ccRCC (786‐O) cell line was shown to result in a temsirolimus‐resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus‐resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.

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“…The patient was found to have a germline TSC1 mutation without other characteristics of a TSC tumour. 99 Conflicts of interest and sources of funding: This work was supported in part by Niigata Foundation for the Promotion of Medicine (2015, to RO), Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (No. JP20K07404, to RO), and the Swiss National Science Foundation grant (No.…”

Section: Treatment Of Metastatic Chromophobe Rccmentioning

confidence: 99%

Chromophobe renal cell carcinoma: current and controversial issues

Moch

Ohashi

2021

Pathology

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It has been 35 years since Professor Thoenes and his colleagues discovered chromophobe renal cell carcinoma (RCC). Since then, our knowledge about this tumour entity has changed and novel tumour entities have been discovered. The aim of this review is to discuss recent molecular findings and open questions in diagnosing chromophobe-like/oncocytic neoplasms. The broader differential diagnosis of chromophobe-like and oncocytomalike neoplasms includes SDH-deficient renal cell carcinoma, fumarate hydratase (FH) deficient RCC, epitheloid angiomyolipoma ('oncocytoma like'), MiT family translocation RCC and the emerging entity of eosinophilic solid and cystic renal cell carcinoma. After separation of these tumours from chromophobe RCC, it becomes evident that chromophobe RCC are low malignant tumours with a 5-6% risk of metastasis. Recent next generation sequencing (NGS) and DNA methylation profiling studies have confirmed Thoenes' theory of a distal tubule derived origin of chromophobe RCC and renal oncocytomas. Comprehensive genomic analyses of chromophobe RCC have demonstrated a low somatic mutation rate and identified TP53 and PTEN as the most frequently mutated genes, whereas 'unclassified' RCC with oncocytic or chromophobe-like features can show somatic inactivating mutations of TSC2 or activating mutations of MTOR as the primary molecular alterations. For the future, it would be desirable to create a category of 'oncocytic/chromophobe RCC, NOS' with the potential of further molecular studies for identification of TSC1/2 mutations in these rare tumours.

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A family case with germlineTSC1and mtDNA mutations developing bilateral eosinophilic chromophobe renal cell carcinomas without other typical phenotype of tuberous sclerosis

Cited by 7 publications

References 26 publications

SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers

SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers

Functional and genomic characterization of patient‐derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma

Chromophobe renal cell carcinoma: current and controversial issues

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