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Metastatic clear cell renal cell carcinoma to the forearm without identifiable primary renal mass.

ABSTRACT: Kidney cancer is the ninth most common malignancy in the United States. Most kidney cancers are clear cell renal cell carcinoma (RCC) and arise as solid tumors from kidney parenchyma. In the setting of metastatic disease, a primary renal tumor is usually identified, and metastases are often to lung, bone, liver, and brain. Metastatic RCC without an identifiable solid kidney tumor is exceedingly rare. We report the case of a 52 year old male with a rare cutaneous RCC metastasis without an identifiable primary renal tumor.

SUBMITTER: Walton J

PROVIDER: S-EPMC6699464 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Metastatic clear cell renal cell carcinoma to the forearm without identifiable primary renal mass.

Walton John J Li Jinhong J Clifton Marisa M MM Mori Ryan L RL Park Alyssa M AM Sumfest Joel M JM

Urology case reports 20190806

Kidney cancer is the ninth most common malignancy in the United States. Most kidney cancers are clear cell renal cell carcinoma (RCC) and arise as solid tumors from kidney parenchyma. In the setting of metastatic disease, a primary renal tumor is usually identified, and metastases are often to lung, bone, liver, and brain. Metastatic RCC without an identifiable solid kidney tumor is exceedingly rare. We report the case of a 52 year old male with a rare cutaneous RCC metastasis without an identif ...[more]

PMID: 31440453

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Project description:BackgroundThe metabolic enzyme nicotinamide-N-methyltransferase (NNMT) is highly expressed in various cancer entities, suggesting tumour-promoting functions. We systematically investigated NNMT expression and its metabolic interactions in clear cell renal cell carcinoma (ccRCC), a prominent RCC subtype with metabolic alterations, to elucidate its role as a drug target.MethodsNNMT expression was assessed in primary ccRCC (n = 134), non-tumour tissue and ccRCC-derived metastases (n = 145) by microarray analysis and/or immunohistochemistry. Findings were validated in The Cancer Genome Atlas (kidney renal clear cell carcinoma [KIRC], n = 452) and by single-cell analysis. Expression was correlated with clinicopathological data and survival. Metabolic alterations in NNMT-depleted cells were assessed by nontargeted/targeted metabolomics and extracellular flux analysis. The NNMT inhibitor (NNMTi) alone and in combination with the inhibitor 2-deoxy-D-glucose for glycolysis and BPTES (bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl-sulfide) for glutamine metabolism was investigated in RCC cell lines (786-O, A498) and in two 2D ccRCC-derived primary cultures and three 3D ccRCC air-liquid interface models.ResultsNNMT protein was overexpressed in primary ccRCC (p = 1.32 × 10-16 ) and ccRCC-derived metastases (p = 3.92 × 10-20 ), irrespective of metastatic location, versus non-tumour tissue. Single-cell data showed predominant NNMT expression in ccRCC and not in the tumour microenvironment. High NNMT expression in primary ccRCC correlated with worse survival in independent cohorts (primary RCC-hazard ratio [HR] = 4.3, 95% confidence interval [CI]: 1.5-12.4; KIRC-HR = 3.3, 95% CI: 2.0-5.4). NNMT depletion leads to intracellular glutamine accumulation, with negative effects on mitochondrial function and cell survival, while not affecting glycolysis or glutathione metabolism. At the gene level, NNMT-depleted cells upregulate glycolysis, oxidative phosphorylation and apoptosis pathways. NNMTi alone or in combination with 2-deoxy-D-glucose and BPTES resulted in inhibition of cell viability in ccRCC cell lines and primary tumour and metastasis-derived models. In two out of three patient-derived ccRCC air-liquid interface models, NNMTi treatment induced cytotoxicity.ConclusionsSince efficient glutamine utilisation, which is essential for ccRCC tumours, depends on NNMT, small-molecule NNMT inhibitors provide a novel therapeutic strategy for ccRCC and act as sensitizers for combination therapies.

Dataset Information

Metastatic clear cell renal cell carcinoma to the forearm without identifiable primary renal mass.

Publications

Metastatic clear cell renal cell carcinoma to the forearm without identifiable primary renal mass.

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