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TFE3-fusions are known to drive both epithelial and mesenchymal renal tumors. Here, the authors generate a transgenic mouse model of renal tumorigenesis expressing the human SFPQ-TFE3 fusion, showing that the fusion regulates mTORC1 activity and induces lineage plasticity.

The field of urology has undergone massive changes in the 10 years sinceNature Reviews Urology launched as Nature Clinical Practice Urology. In this Viewpoint, members of the Nature Reviews Urologyadvisory board describe what they think has been the biggest change or issue in urology over the past decade, and give their predictions for the direction of the field over the next 10 years.

The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.

Rare subtypes of renal cancers can be difficult to diagnose. Here, the authors use transcriptional analysis to show utility in aiding histological classification.

Each of the kidney cancer genes identified so far interact with cell metabolism pathways involved in energy, nutrient, iron or oxygen sensing. Here, Linehan and colleagues argue that targeting the fundamental cell metabolic abnormalities provides a unique opportunity to develop novel forms of therapy for this disease.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

Chemoproteomic mapping of fumarate sensitive cysteines in a hereditary leiomyomatosis and renal cell carcinoma cell line revealed a critical cysteine in the protein–protein interaction interface of the SWI–SNF complex.

Up to half of patients with VHL develop malignant renal lesions. Urologists handling these cases are faced with the challenge of optimizing control of often bilateral multifocal tumors while maximizing preservation of kidney function. Robert Grubb and colleagues assess the relative merits of different management strategies, and present the molecular processes underlying VHL that might be targeted by new treatments.

Recent advances have been exciting in the genomics of and targeted therapeutics for renal cell carcinoma (RCC). New agents have been approved for advanced RCC, a novel agent targeting hypoxia-inducible factor 2α has shown considerable promise and molecular characterization of papillary RCC provides the foundation for development of targeted therapeutic approaches for this disease.

A multi-ancestry genome-wide association meta-analysis of kidney cancer identifies 63 regions associated with disease susceptibility including one locus that was associated with increased risk in individuals with African ancestry.

Tumour cells with defective mitochondria are found to use glutamine-dependent reductive carboxylation, rather than oxidative metabolism, as the major pathway of citrate and lipid formation.

In this Review, Bratslavsky and Linehan address the management of the challenging group of patients with bilateral, multifocal, recurrent renal cell carcinoma. They discuss the treatment options and outcomes for these patients, highlight the importance of maximal renal preservation, and outline a management strategy developed from their own experience in treating these patients.

Multiple cellular pathways are altered in cancer and identifying them is relevant for prognosis and therapy. Here, the authors develop Benchmark and Pathway Ensemble Tool (PET), two computational approaches to optimise pathway discovery in cancer and predict related biomarkers and therapeutic avenues.

Reprogrammed metabolism has been long recognized as a driver of kidney cancer progression, prompting efforts to develop metabolic targeted therapies against this disease. Evidence offers further clarity on the metabolic phenotypes associated with aggressive disease, expanding the potential target space for attacking these tumours at their metabolic roots.

Identification of the tumor suppressor FLCN as an intracellular inhibitor of LDHA and a regulator of the Warburg effect provides a new paradigm for the regulation of glycolysis.

Birt–Hogg–Dubé (BHD) syndrome is an inherited renal cancer syndrome caused by germline mutations in theFLCNgene on chromosome 17. Manifestations include benign cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumours. In this Review, Schmidt and Linehan provide an overview of BHD syndrome, discussing the molecular genetics, diagnosis, and management of this rare disorder.

Blood and lymphatic vessels bear a strong resemblance but do not share a lumen, thus maintaining their distinct functions. Here, the authors describe that Folliculin, a tumor suppressor, prevents the fusion of these vessels during development by limiting the plasticity of venous and lymphatic endothelial cells.

Radiofrequency ablation and cryoablation of the small renal mass have emerged as treatment options for patients who are not surgical candidates or who elect not to undergo surgery. Besides concerns regarding the definition of treatment success and the difficulty of salvage procedures, incomplete ablation might potentially create a tumour microenvironment that promotes cancer progression.

Clear cell renal cell carcinoma (CCRCC) is characterized by mutation of the VHL gene and loss of a segment of chromosome 3. A new study using multi-region exome sequencing has identified substantial intratumoral heterogeneity within large primary CCRCCs, which has profound implications for understanding tumor evolution and for developing effective therapies.

For decades, complete removal of the kidney with all the contents of the Gerota's fascia (including the adrenal gland) has been a standard procedure for treating renal cell carcinoma (RCC). Two recent articles argue against routine adrenalectomy, and encourage adrenal preservation for the vast majority of patients with RCC.

In a mouse model of breast cancer, a low-protein diet induces engulfment activities and mTORC1 signalling in tumour-associated macrophages to suppress engulfment-dependent mTORC1 signalling in MYC-overexpressing cancer cells through cell competition, serving as an innate immune defence mechanism to slow tumour growth.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited disease characterized by skin and uterine leiomyomas, and kidney tumors that are often aggressive. In this Review the authors discuss the etiology of this inherited kidney cancer and the diagnosis and management of affected families. The genetic changes underlying HLRCC and pathophysiological mechanisms behind the development of this disease are also reviewed.

Several advances in kidney cancer have occurred over the past decade, including the discovery of mutations in chromatin remodelling genes and genomic heterogeneity in clear cell renal cell carcinoma (ccRCC). Altered metabolic patterns in ccRCC and papillary RCC have become apparent, and new drugs for ccRCC have been approved.

Analysing multiple tumours from the same patient permits the study of the germline contribution to cancer. Here, the authors sequence multiple renal tumours from VHL patients and find that intra-patient tumours are clonally distinct but share some genetic features, suggesting that patient-specific factors influence tumour formation.

This Review by Ricketts and Linehan comprehensively summarizes the findings of The Cancer Genome Atlas analyses of renal cell carcinoma and their clinical implications. The authors highlight unique and shared features of the tumour histological subtypes, their predictive power and their possible utility as therapeutic targets.

Hsp90 is required for the folding, stability and activity of several drivers of oncogenesis. Here the authors show that Folliculin-interacting proteins (FNIP) 1 and 2, whose expression correlates with the cellular response to Hsp90 inhibitors, are co-chaperones of Hsp90 that function by inhibiting its ATPase activity.

A randomized phase III trial comparing pazopanib with sunitinib in patients with advanced clear cell renal cell carcinoma showed that although progression-free survival and overall survival were similar, pazopanib was better tolerated. Recent advances in genomics and metabolomics have provided novel insights that could be leveraged to improve therapy.

A mouse model with combined renal epithelium-specific deletion of Vhl, Trp53 and Rb1 that develops clear-cell renal cell carcinoma provides a research tool for investigating the mechanisms that drive this cancer, and for evaluating the efficacy of novel therapeutic agents.

Three reports from the TRACERx Renal study delineate the precise origin and evolution of clear cell renal cell carcinoma in minute detail. The insights gained from these studies might provide improved disease prognostics and identify novel therapeutic targets.

A recently published study has evaluated metabolism in human clear cell renal carcinomas (ccRCCs) using intraoperative [¹³C]glucose infusion during surgical procedures. The findings demonstrate aerobic glycolysis and repression of the Krebs cycle, confirming the existence of the Warburg effect in ccRCC tumours in vivo.

Heat shock protein 90 (HSP90) plays a major role in many cancers, including tumors of the prostate and kidney. Its function in cell regulation makes it a potential target for treatments against cancer. This Review provides insights into the role of HSP90 in urologic cancers and discusses the data from clinical trials examining the use of HSP90 inhibitors in the treatment of patients with urologic cancers.

In this Review, Kauffman and colleagues summarize contemporary understanding of the molecular biology underlyingTFE3 and TFEB gene-fusion-associated (translocation) renal cell carcinomas. They discuss the candidate mechanisms and signalling pathways thought to contribute to the oncogenesis of these tumours, and describe TFE3 and TFEBfusion genetic organization.

Potassium ions released by necrotic cells in tumours impair T cell function by increasing the intracellular potassium concentration in vitro and in vivo.