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| Open AccessGenetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q
The genetic and epigenetic predisposition of bilateral Wilms tumour remains to be investigated. Here, the authors perform multiomics analysis and identify the predominant genetic and epigenetic events associated with bilateral Wilms tumour predisposition.
- Andrew J. Murphy
- , Changde Cheng
- & Xiang Chen
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Article
| Open AccessGenomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort
Renal cell carcinoma (RCC) subtypes are associated with different molecular alterations and clinical outcomes, but they need to be characterised in diverse cohorts. Here, the authors perform genomic, transcriptomic, and epigenomic profiling in a large cohort of Japanese RCC cases, and identify epi-subtypes associated with a particular immune environment.
- Akihiko Fukagawa
- , Natsuko Hama
- & Tatsuhiro Shibata
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Article
| Open AccessDelineating the interplay between oncogenic pathways and immunity in anaplastic Wilms tumors
Treatment of diffuse anaplastic Wilms tumours (DAWT) remains a challenge. Here, the authors perform multi-omic analysis and identify a desert-like DAWT subtype accounting for one third of DAWT cases and suggest treating them with HDAC and/or WEE1 inhibitors.
- Xiaoping Su
- , Xiaofan Lu
- & Gabriel G. Malouf
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Article
| Open AccessSETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer
SET domain–containing 2 (SETD2) is reported as an immunosuppressor in clear cell renal cell carcinoma (ccRCC). Here the authors show that SETD2 loss enhances de novo sphingomyelin biosynthesis during the transition from polycystic kidney disease to ccRCC.
- Hanyu Rao
- , Changwei Liu
- & Xianting Ding
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Article
| Open AccessTargetable NOTCH1 rearrangements in reninoma
Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of NOTCH1 rearrangements.
- Taryn D. Treger
- , John E. G. Lawrence
- & Tanzina Chowdhury
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Article
| Open AccessProteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor
Many clear cell renal cell carcinoma (ccRCC) patients do not respond or develop resistance to tyrosine kinase inhibitors, such as Sunitinib. Here, the authors perform a proteogenomics analysis of Chinese ccRCC patients treated with Sunitinib and develop a multi-omics classifier to distinguish responders from non-responders.
- Hailiang Zhang
- , Lin Bai
- & Chen Ding
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Article
| Open AccessSMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance
The molecular mechanisms involved in the development of SMARCB1-deficient renal medullary carcinomas (RMCs) remain to be characterised. Here, the authors integrated RMC omics data to show that ferroptosis resistance contributes to transformation of renal thick ascending limb cells into several RMC cell states.
- Bujamin H. Vokshi
- , Guillaume Davidson
- & Gabriel G. Malouf
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Article
| Open AccessEpigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
Tumour heterogeneity in clear cell renal cell carcinoma (ccRCC) remains to be investigated. Here, the integration of spatial omics, transcriptional and chromatin accessibility profiling at the single-nucleus level and bulk proteogenomics data reveal markers and pathways important for ccRCC.
- Yige Wu
- , Nadezhda V. Terekhanova
- & Feng Chen
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Article
| Open AccessEpigenomic charting and functional annotation of risk loci in renal cell carcinoma
The epigenomic landscape of renal cell carcinoma (RCC) remains to be explored. Here, integrative epigenomic analysis of primary human RCC samples and RCC GWAS risk SNPs identifies transcription-factor specific subtypes and enrichment of risk variants in allelically-imbalanced peaks.
- Amin H. Nassar
- , Sarah Abou Alaiwi
- & Matthew L. Freedman
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Article
| Open AccessProteogenomic characterization of MiT family translocation renal cell carcinoma
The molecular landscape of microphthalmia transcription factor family translocation renal cell carcinoma tumours remain to be characterised. Here, the authors perform proteogenomic analysis and reveal dysregulation of DNA repair, mTOR signalling and metabolic processes.
- Yuanyuan Qu
- , Xiaohui Wu
- & Chen Ding
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Article
| Open AccessAn mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.
- Kaushal Asrani
- , Juhyung Woo
- & Tamara L. Lotan
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Article
| Open AccessMolecular characterization of renal cell carcinoma tumors from a phase III anti-angiogenic adjuvant therapy trial
Based on the S-TRAC results, sunitinib is approved as adjuvant treatment for adult patients at high risk of recurrent RCC following nephrectomy. Here, the authors report the results of an integrated multi-omics tumor analysis of 171 patients from the trial and identify specific molecular subtypes as well as potential new targets.
- Robert J. Motzer
- , Jean-François Martini
- & Alain Ravaud
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Article
| Open AccessA transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma
Metastatic clear cell renal cell carcinoma has a poor prognosis. Here, the authors use single cell RNA-seq to show a distinct gene expression signature in the primary tumour of metastatic patients, and highlights immune cell receptor interactions as potential therapeutic targets.
- Adele M. Alchahin
- , Shenglin Mei
- & Ninib Baryawno
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Article
| Open AccessSingle-cell chromatin accessibility landscape in kidney identifies additional cell-of-origin in heterogenous papillary renal cell carcinoma
The heterogeneity of cell-of-origin for papillary renal cell carcinoma (pRCC) remains unknown. Here, with single-cell ATAC-seq from normal human kidney cells and ATACseq profiles from pRCC samples, the authors show that pRCC can originate from kidney collecting duct principal cells and this subtype is associated with advanced pRCC.
- Qi Wang
- , Yang Zhang
- & Jingping Yang
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Article
| Open AccessPilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma
Anti-CTLA4 therapy has not been comprehensively explored for the treatment of metastatic renal cell carcinoma (mRCC). Here, in a pilot study of anti-CTLA4 therapy with or without cryoablation in mRCC, the authors report that the combination is feasible and enhances immune infiltration in patients with metastatic clear cell histology.
- Matthew T. Campbell
- , Surena F. Matin
- & Padmanee Sharma
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Article
| Open AccessDeterminants of renal cell carcinoma invasion and metastatic competence
Tumour thrombi (TT) are intravascular extensions of renal cell carcinomas (RCC) which often lead to distant metastases. Here the authors examine the determinants of vascular invasion and metastasis in a unique cohort of RCC patients with TT using multi-region genomics and in vivo models.
- Kangsan Kim
- , Qinbo Zhou
- & Srinivas Malladi
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Article
| Open AccessProfiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy
Targeting the inhibitory receptors (IRs) LAG-3, TIM-3 and TIGIT is a promising immune-oncology approach and the identification of biomarkers of response is crucial. Here, the authors apply automated single-cell count for these IRs in human renal cell carcinoma and investigate the immunogenomic landscape of the disease.
- Kimiharu Takamatsu
- , Nobuyuki Tanaka
- & Mototsugu Oya
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Article
| Open AccessIntegrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma
TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare subtype of kidney cancer with no standard treatment options for the advanced disease. Here, the authors perform genomic and transcriptomic profiling of 63 untreated primary TFE3-tRCC tumours and reveal potential therapeutic targets.
- Guangxi Sun
- , Junru Chen
- & Hao Zeng
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Article
| Open AccessIntegrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma
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.
- Ziad Bakouny
- , David A. Braun
- & Toni K. Choueiri
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Article
| Open AccessHIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice
Genetic inactivation of VHL leads to stabilization of HIF-1α/HIF-2α and is associated with clear cell renal cell carcinoma (ccRCC) initiation and progression. Using an autochthonous mouse model of ccRCC with Vhl deletion, here the authors show that HIF-1α is necessary for tumor formation, while HIF-2α deletion has only a moderate effect.
- Rouven Hoefflin
- , Sabine Harlander
- & Ian J. Frew
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Article
| Open AccessThe genomic and epigenomic evolutionary history of papillary renal cell carcinomas
Many tumours are heterogenous, which calls into question whether multiple biopsies are required to accurately assess the cancer. Here, the authors show that papillary renal cell carcinoma is clonal in nature, suggesting that in this cancer one biopsy is sufficient for diagnosis and molecular analyses.
- Bin Zhu
- , Maria Luana Poeta
- & Maria Teresa Landi
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Article
| Open AccessComputational analysis of pathological images enables a better diagnosis of TFE3 Xp11.2 translocation renal cell carcinoma
Translocation renal cell carcinoma is an aggressive form of renal cancer that is often misdiagnosed to other subtypes. Here the authors demonstrated that by using machine learning and H&E stained whole-slide images, an accurate diagnose of this particular type of renal cancer can be achieved.
- Jun Cheng
- , Zhi Han
- & Jie Zhang
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Article
| Open AccessInhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients
Cancer stem cells are thought to be largely resistant to treatment and can be responsible for tumour recurrence. Here, using renal cancer organoids, self-renewing sphere cultures and PDX from patients, the authors show that the proliferation of stem cells within organoids, PDX and spheres can be blocked by the concomitant inhibition of the NOTCH and WNT pathways.
- Annika Fendler
- , Daniel Bauer
- & Walter Birchmeier
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Article
| Open AccessIntegrative genomic study of Chinese clear cell renal cell carcinoma reveals features associated with thrombus
The genomic heterogeneity of clear cell renal cell carcinoma (ccRCC) across populations is poorly understood. Here, the authors analyse a cohort of Chinese ccRCC cases revealing a mutational signature associated with aristolochic acid exposure, and higher mutational burden and enrichment for BAP1 and SETD2 mutations in ccRCC cases associated with tumor thrombus.
- Xiang-Ming Wang
- , Yang Lu
- & Lu-Lin Ma
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Article
| Open AccessPBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth
Acetylation of p53 is critical for its transcriptional activity and its tumour suppressive function. Here, the authors show that PBRM1 is a reader protein for p53′s C-terminal domain acetylation on lysine 382 through its bromodomain 4 and that mutations in this domain leads to compromised tumour suppressive function and renal tumour growth.
- Weijia Cai
- , Liya Su
- & Haifeng Yang
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Article
| Open AccessA GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.
- Yilong Zou
- , Michael J. Palte
- & Stuart L. Schreiber
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Article
| Open AccessClonal architectures predict clinical outcome in clear cell renal cell carcinoma
Clear cell renal cell carcinoma (ccRCC) is a urogenital cancer with a well-defined genetic landscape. Here, the authors analyse the clonal architecture of ccRCC patients from three populations, and find prognostic subtypes linked to immune infiltrates and clonal architecture.
- Yi Huang
- , Jiayin Wang
- & Baifeng Zhang
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Article
| Open AccessA KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma
Super enhancers are frequently involved in the dysregulation of gene expression in cancer. Here, in kidney cancer, a super enhancer is shown to drive the expression of KLF6, which alters the expression of lipid metabolism genes and promotes tumorigenesis.
- Saiful E. Syafruddin
- , Paulo Rodrigues
- & Sakari Vanharanta
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Article
| Open AccessLoss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis
Mutations in VHL have been linked to clear cell renal cancer, but the molecular mechanisms involved remain unclear. Here the authors generate a mouse model closely mimicking the human disease and show that VHL loss induces DNA replication stress that is rescued by the concomitant loss of PBRM1 permitting transformation.
- Judit Espana-Agusti
- , Anne Warren
- & Athena Matakidou
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Article
| Open AccessHIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism
Clear cell renal cancers (ccRCC) display elevated intracellular lipid storage. Here the authors show that such lipid accumulation is due to the repression of carnitine palmitoyltransferase 1A (CPT1A) enzyme that impairs fatty acid (FA) transport into the mitochondrion resulting in reduced FA beta oxidation.
- Weinan Du
- , Luchang Zhang
- & Scott M. Welford
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Article
| Open AccessEvidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells
Renal angiomyolipomas (AML) contain a mix of clonal tumour cells. Here, through reverse tumour engineering experiments, mouse genetics and analyses of human AML tumours, the authors provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells.
- Ana Filipa Gonçalves
- , Mojca Adlesic
- & Ian J. Frew
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Article
| Open AccessAndrogen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma
The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.
- Qingbo Huang
- , Yin Sun
- & Chawnshang Chang
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Article
| Open AccessNegative regulation of EGFR signalling by the human folliculin tumour suppressor protein
Folliculin is a known tumour suppressor but the molecular mechanisms behind this function are unclear. Here the authors show that Folliculin regulates EGFR signalling by modulating its Rab7a-dependent trafficking.
- Laura A. Laviolette
- , Julien Mermoud
- & Othon Iliopoulos
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Article
| Open AccessMYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma
Renal cell carcinoma (RCC) is a common and aggressive malignancy. Here, the authors generate two mouse models of the most common RCC subtypes: the human papillary RCC throughMYC activation and clear cell RCC through MYC activation combined with Vhl and Cdkn2adeletion.
- Sean T. Bailey
- , Aleisha M. Smith
- & William Y. Kim
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Article
| Open AccessAnalysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection
Cell lines are central to cancer research, but knowing which cell lines are the best representative of actual tumours is a major challenge. Here the authors provide a resource assessment of 65 renal cell lines to assist researchers in selecting suitable lines for studying specific renal carcinoma subtypes.
- Rileen Sinha
- , Andrew G. Winer
- & A. Ari Hakimi
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Article
| Open AccessA feed-forward loop between lncARSR and YAP activity promotes expansion of renal tumour-initiating cells
Renal tumour-initiating cells (T-ICs) contribute to tumour initiation and progression. Here, the authors show that lncARSR regulates TICs by blocking LATS1-induced YAP phosphorylation facilitating YAP nuclear translocation, which promotes lncARSR transcription, thus forming a feed-forward circuit to promote TIC expansion.
- Le Qu
- , Zhenjie Wu
- & Linhui Wang
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Article
| Open AccessGenetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer
Genome-wide association studies have identified multiple loci associated with the risk of developing renal cancer. Here, the authors show that one of these loci generates open chromatin, which enhances the binding of HIF and HIF-mediated transactivation ofMYC.
- Steffen Grampp
- , James L. Platt
- & Johannes Schödel
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Article
| Open AccessMolecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets
A subset of renal cell carcinomas have uncertain histology and are aggressive in nature. Here, the authors examine this group of unclassified renal cancers using genomics techniques and identify further subclasses of the tumours that have differing prognoses.
- Ying-Bei Chen
- , Jianing Xu
- & James J. Hsieh
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Article
| Open AccessAtezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma
Cancer immunotherapy can be used in combination with other therapies for a better response. Here, the authors conduct a phase Ib clinical study and report the clinical activity and the immune response of the anti-PDL1 agent, atezolizumab, in combination with bevacizumab in ten patients with metastatic renal cell carcinoma.
- Jeffrey J. Wallin
- , Johanna C. Bendell
- & David F. McDermott
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Article
| Open AccessFunctional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41
A common susceptibility haplotype for renal cell carcinoma is located on chromosome 12p12.1. Here, the authors show that the variant rs7132434 alters binding of the AP-1 transcription factor, which increases the expression of BHLHE41in renal cells.
- Pierre Bigot
- , Leandro M. Colli
- & Stephen J. Chanock
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Article
| Open AccessSpatial niche formation but not malignant progression is a driving force for intratumoural heterogeneity
It has been increasingly recognised that tumours are not made up of a homogeneous population of cells. Here, the authors show heterogeneous expression of five protein markers in renal cell cancer and demonstrate that the progression of the tumour does not influence the degree of heterogeneity in the tumour.
- Rouven Hoefflin
- , Bernd Lahrmann
- & Stefan Duensing
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Article
| Open AccessPatient-specific factors influence somatic variation patterns in von Hippel–Lindau disease renal tumours
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.
- Suzanne S. Fei
- , Asia D. Mitchell
- & Paul T. Spellman
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Article
| Open AccessLysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer
Acquisition of mesenchymal properties by cancer cells is a critical event for the development of malignancy. Here, the authors show that in renal cancer cells, lysosphosphatidic acid does not utilize the RhoA pathway but specifically activates the Arf6 mesenchymal pathway via its GPCRs and EFA6 to promote invasion, metastasis and drug resistance.
- Shigeru Hashimoto
- , Shuji Mikami
- & Hisataka Sabe
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Article
| Open AccessMLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours
Wilms tumour is a rare renal neoplasm that primarily affects children but the genomic changes responsible for its development are currently largely unknown. In this study, the authors identify somatic mutations of the MLLT1gene that are potentially involved in the aetiology of a subset of Wilms tumours.
- Elizabeth J. Perlman
- , Samantha Gadd
- & Malcolm A. Smith
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Article
| Open AccessRecurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney
The genetic basis of clear cell sarcomas of the kidney is not well understood. In this study, Roy et al. perform whole-exome and RNA sequencing of these tumours and identify recurrent internal tandem duplications in BCOR, a key constituent of a variant polycomb repressive complex.
- Angshumoy Roy
- , Vijetha Kumar
- & D. Williams Parsons
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Article
| Open AccessA CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma
Using molecular markers is a useful way to predict the prognosis of cancer patients. Here, Wei et al.describe a five gene methylation signature that can predict the prognosis of renal clear cell cancer and validate its use in multiple patient cohorts.
- Jin-Huan Wei
- , Ahmed Haddad
- & Jun-Hang Luo
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Article
| Open AccessRecurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution
Papillary renal cell carcinoma (pRCC) is a subtype of kidney cancer characterized by highly variable clinical behaviour. Here the authors sequence either the genomes or exomes of 31 pRCCs and identify several genes in sub-clones and large copy number variants in major clones that may be important drivers of pRCC.
- Michal Kovac
- , Carolina Navas
- & Ian Tomlinson
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Article
| Open AccessFumarate induces redox-dependent senescence by modifying glutathione metabolism
Fumarate hydratase (FH) mutations are associated with renal cancer. Here, Zheng et al. use metabolomic and analytical chemistry approaches to reveal that fumarate accumulated due to FH loss covalently modifies intracellular glutathione, leading to oxidative stress and senescence.
- Liang Zheng
- , Simone Cardaci
- & Eyal Gottlieb
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Variation in genomic landscape of clear cell renal cell carcinoma across Europe
Renal cancer accounts for 2.4% of all adult cancers and its incidence is increasing worldwide. Here, the authors carry out genome and transcriptome sequencing of clear cell renal cell carcinomas (ccRCCs) and highlight genomic aberrations and biological pathways underlying ccRCC tumorigenesis.
- Ghislaine Scelo
- , Yasser Riazalhosseini
- & G. Mark Lathrop