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Wilms tumor (WT) accounts for approximately 95 % of all pediatric renal tumors, with a peak incidence between 2 and 3 years of age. It occurs in sporadic and congenital forms, the latter often occurring before 1 year of age. Incidence declines with age, and WT rarely is observed in adults. WT is an embryonal tumor of the kidney caused by aberrant proliferation of early metanephric kidney cells. It can arise from more than one developmental error and therefore several subtypes can be defined. WT1 , a zinc-finger transcription factor, was identified as the first WT gene. Other genes frequently altered somatically in subsets of WT are CTNNB1 and WTX ; both genes influence the Wnt signalling pathway. Imprinting alterations of genes in 11p15 are also observed in a subset of WTs. Other pediatric renal tumors occur less often, e.g. malignant rhabdoid tumor of the kidney, clear-cell sarcoma, desmoplastic small-round-cell tumors, congenital mesoblastic nephroma, renal cell carcinoma of childhood, renal primitive neuroectodermal tumors, renal medullary carcinoma, and synovial sarcoma of the kidney. In most of these, characteristic genetic alterations have been identified that help in the unequivocal diagnosis of these childhood renal cancers that are often difficult to distinguish.

Understanding tumor origins and the similarities and differences between organ-specific cancers is important for determining treatment options. Young et al. generated more than 72,000 single-cell transcriptomes from healthy and cancerous human kidneys. From these data, they determined that Wilms tumor, a pediatric kidney cancer, originates from aberrant fetal cells, whereas adult kidney cancers are likely derived from a specific subtype of proximal convoluted tubular cell. Science , this issue p. 594 Single-cell mRNAs of normal and cancerous kidney cells reveal the cellular identity of childhood and adult tumors. Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.

Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. Paediatric kidney tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug sensitivities. Using single cell RNA-sequencing and high resolution 3D imaging, we further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like cells. Our organoid biobank captures the heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterised models for basic cancer research, drug-screening and personalised medicine. Pre-clinical cell culture models capturing the heterogeneity of childhood kidney tumours are limited. Here, the authors establish and characterise an organoid biobank of tumour and matched normal organoid cultures from over 50 children with different subtypes of kidney cancer.

Wilms tumour is the most common renal malignancy of childhood. The disease is curable in the majority of cases, albeit at considerable cost in terms of late treatment-related effects in some children. However, one in ten children with Wilms tumour will die of their disease despite modern treatment approaches. The genetic changes that underpin Wilms tumour have been defined by studies of familial cases and by unbiased DNA sequencing of tumour genomes. Together, these approaches have defined the landscape of cancer genes that are operative in Wilms tumour, many of which are intricately linked to the control of fetal nephrogenesis. Advances in our understanding of the germline and somatic genetic changes that underlie Wilms tumour may translate into better patient outcomes. Improvements in risk stratification have already been seen through the introduction of molecular biomarkers into clinical practice. A host of additional biomarkers are due to undergo clinical validation. Identifying actionable mutations has led to potential new targets, with some novel compounds undergoing testing in early phase trials. Avenues that warrant further exploration include targeting Wilms tumour cancer genes with a non-redundant role in nephrogenesis and targeting the fetal renal transcriptome.Wilms tumour is the most common renal malignancy of childhood. Here, the authors review the genetic landscape of Wilms tumour and discuss how precision medicine guided by genomic information might lead to new therapeutic approaches and improve patient survival.

On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP–RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP–RTSG pathology panel.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.

This study shows that Dis3l2 is the 3′–5′ exonuclease that mediates the degradation of uridylated precursor let-7 microRNA; this is the first physiological RNA substrate identified for this new exonuclease, which causes the Perlman syndrome of fetal overgrowth and Wilms’ tumour susceptibility when mutated. Function of Perlman syndrome exonuclease The Lin28-let-7 signalling cascade has been linked to stem cell function, cancers and various aspects of cellular metabolism. The pluripotency factor Lin28 recruits the 3′ terminal uridylyl transferases that add an oligouridine tail to let-7 precursor RNA. Here Richard Gregory and colleagues demonstrate that Dis3l2, a protein mutated in Perlman syndrome of fetal overgrowth and predisposition to Wilms' tumour, is the exonuclease that mediates the degradation of uridylated pre-let-7 in mouse embryonic stem cells. The identification of a decay pathway for uridylated RNAs raises the possibility that this type of post-transcriptional regulation might occur more widely. The pluripotency factor Lin28 blocks the expression of let-7 microRNAs in undifferentiated cells during development, and functions as an oncogene in a subset of cancers 1 . Lin28 binds to let-7 precursor (pre-let-7) RNAs and recruits 3′ terminal uridylyl transferases to selectively inhibit let-7 biogenesis 2 , 3 , 4 . Uridylated pre-let-7 is refractory to processing by Dicer, and is rapidly degraded by an unknown RNase 5 . Here we identify Dis3l2 as the 3′–5′ exonuclease responsible for the decay of uridylated pre-let-7 in mouse embryonic stem cells. Biochemical reconstitution assays show that 3′ oligouridylation stimulates Dis3l2 activity in vitro , and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3′ oligouridylation as an RNA decay signal for Dis3l2, and identifies the first physiological RNA substrate of this new exonuclease, which is mutated in the Perlman syndrome of fetal overgrowth and causes a predisposition to Wilms’ tumour development 6 .

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and ‘hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

Elizabeth Perlman and colleagues use genome-wide sequencing, RNA expression, DNA copy number and methylation analyses to characterize the genomic landscape of Wilms tumors. Their integrated analyses implicate two major classes of genetic changes in Wilms tumors that preserve the progenitor state and/or interrupt normal kidney development. We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors ( WT1 , CTNNB1 , AMER1 , DROSHA , DGCR8 , XPO5 , DICER1 , SIX1 , SIX2 , MLLT1 , MYCN , and TP53 ), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR , BCORL1 , NONO , MAX , COL6A3 , ASXL1 , MAP3K4 , and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

Wilms tumor (WT) is a common renal malignancy in pediatric patients. Interleukin (receptors) (IL(R)s) play significant roles in tumor biology, however, their specific involvement in WT remains inadequately understood. We employed univariate Cox regression analysis to screen for certain IL(R) genes associated with prognosis and then analyzed their expression patterns. A prognostic model was constructed based on five selected IL(R)s using the LASSO Cox regression algorithm. To further elucidate the relationship between the prognostic model and the immune microenvironment, we conducted immune-related analyses. Additionally, we performed experiments to verify the roles of IL20RA and IL19 in WT. Finally, CNV, methylation and pan-cancer analysis were performed for IL19 and IL20RA . Our analysis ultimately identified five genes associated with prognosis: IL20RA, IL19, IL24, IL11 and IL17RD . The prognostic model incorporating these five genes demonstrated robust predictive power in both training and validation cohorts. Notably, IL19 and IL20RA were found to promote epithelial-mesenchymal transition (EMT) through the STAT3/SNAIL pathway, thereby contributing to tumor progression. Furthermore, significant differences in immune function and checkpoint expression were observed between the two groups. The high-risk group exhibiting a lower TIDE score, which suggests a potentially better response to immunotherapy. This study introduces a novel IL(R)-based prognostic signature for WT, highlighting IL20RA as a potential therapeutic target. These findings offer valuable insights for future studies on WT.