Reem Al-Saadi

Mutations in the transcription factor gene Wilms Tumor 1 ( WT1 ) are one of the leading causes of congenital glomerular disease, characterized by severe urinary protein loss and glomerular scarring. No disease-modifying therapies exist for WT1 glomerulopathies, and affected children rely on dialysis or kidney transplantation. We evaluated a previously uncharacterized treatment in a mouse model with an orthologous human mutation in Wt1 ( Wt1 ^{+ /R394W} ) that replicates the pathology of WT1 glomerulopathy. Lipid nanocomplexes were engineered to target integrin αvβ3 for efficient delivery of mRNA to primary podocytes and glomerular endothelial cells in vitro. A minimally invasive ultrasound-guided renal artery injection enabled precise and specific kidney localization in vivo, a finding not replicated by systemic administration. Nanocomplex-derived protein localized in glomeruli for up to 7 days in healthy and diseased mice. This platform was then used to perform an interventional preclinical trial in Wt1 ^+/R394W mice, delivering angiopoietin-1 ( Angpt1 ) mRNA, a vascular growth factor critical for glomerular health that is reduced in Wt1 ^+/R394W podocytes. Angpt1 nanocomplex therapy reduced albuminuria, preserved glomerular endothelial integrity, prevented podocyte loss, and alleviated glomerulosclerosis in Wt1 ^+/R394W mice. These findings demonstrate the therapeutic potential of this targeted approach for WT1 glomerulopathy and provide a foundation for clinical translation to improve outcomes in children with glomerular disease.

Contains Supplementary Figures 1-9. Supplementary Figure 1 shows age of diagnosis of children and indel burden and rearrangement burden for tumours from predisposed children versus those with sporadic disease. Supplementary Figure 2 shows genomic evidence for novel predispositions. Supplementary Figure 3 shows global methylation patterns. Supplementary Figure 4 shows differential gene expression. Supplementary Figure 5 shows mutational signatures. Supplementary Figure 6 shows histological subtypes across predispositions and across somatic drivers. Supplementary Figure 7 shows polyclonal versus clonal enrichment of 11p LOH in normal kidneys. Supplementary Figure 8 shows phylogenies in children with multiple neoplasms and either WT1 or TRIM28 predispositions. Supplementary Figure 9 shows phylogenies in children with non WT1/ non TRIM28 predispositions or sporadic disease.

Contains Supplementary Tables 1-8. Supplementary Table 1 shows characteristics of discovery cohort. Supplementary Table 2 shows genes included in predisposition analysis. Supplementary Table 3 shows evidence underlying novel predispositions. Supplementary Table 4 shows variants that would be detectable by current clinical assays. Supplementary Table 5 shows substitutions and indels. Supplementary Table 6 shows rearrangements. Supplementary Table 7 shows 10,000 most variable probes. Supplementary Table 8 shows differentially expressed genes.

BACKGROUND AND SCOPE: Historical data sources for rare cancers are valuable for data-driven research. The International Society of Pediatric Oncology Renal Tumors Study Group (SIOP-RTSG) has been conducting clinical research on pediatric renal tumors for more than 50 years. Since 1993, data have been collected across multiple countries, using standardized paper-based case report forms that were digitally transcribed into electronic databases. Until 2019, prospectively collected data are present in nine different electronic sources from three consecutive clinical studies. More than 10,000 patient cases of kidney cancer in children are registered in totality. However, the necessary merging of numerous sources to answer a research question is repetitive, time consuming, and unsustainable in the long term. SOLUTION: By mapping and formatting the structure of these nine databases, a single database was created that was similar in design to the prospective study database. This allows the data from the past and current studies to be accessed and queried efficiently with standardized syntax and reports. EVALUATION: We validated this new database by reviewing whether uploads were complete and successful, mapped items were coded correctly, or discrepancy appeared in the export. Comparisons with retrospective reports were made to ensure the datasets were reproducible. RELEVANCE: Researchers have access to a large number of patients through this validated aggregated database. Data maintenance and extraction is efficient, and it offers the possibility to complete missing data directly into the central database. This ultimately ensures long-term availability in a secure, flexible, and responsible manner, in accordance with FAIR principles. HOW TO ACCESS/USE: Researchers can send questions to SIOP-RTSG and, if necessary, gain access to the database after short training. Access granted would depend on user's role.

Background: The Improving Population Outcomes for Renal Tumours of childhood (IMPORT) is a prospective clinical observational study capturing detailed demographic and outcome data on children and young people diagnosed with renal tumours in the United Kingdom and the Republic of Ireland. Methods: Data were extracted from the IMPORT database for all newly diagnosed cases of Wilms tumour (WT) registered between November 2012 and December 2022. Kaplan–Meier survival was estimated at one, three and five years. For children aged 0–14 years with unilateral WT, Cox proportional hazards models were used to examine patient/tumour characteristics in relation to the excess hazard of death. Results: Among 620 patients, 570 had unilateral and 50 (8%) bilateral disease; 582 (94%) patients received pre‐operative chemotherapy and 38 (6%) immediate surgery. Median age was 41 months (IQR: 41–65). Median tumour volume at diagnosis was 595 cm ³ (IQR: 348–914) and 228 cm ³ (IQR: 83–535) after pre‐operative chemotherapy, with 123/443 (28%) ≥500 cm ³ . Of 570 patients with unilateral WT, 419 (73.5%) had localised and 151 (26.5%) metastatic disease. Five‐year survival was highest for children aged 0–4 years (94.8%). Five‐year survival by Toronto stage (assessed at nephrectomy) was 97.0% (stage I/yI), 93.8% (stage II/yII), 85.2% (stage III/yIII) and 88.9% (stage IV), and by histology 74.6% (high risk), 95.2% (intermediate risk) and 100% (low risk). In univariate analysis, histological risk group, age (</≥ 4 years), stage and tumour volume ≥500 cm ³ after pre‐operative chemotherapy were significantly associated with excess risk of death. In multivariate modelling, only high‐risk histology (HR 10.8, 95% CI: 4.0–29.1) retained significance. Conclusions: Five‐year survival for children with WT in the United Kingdom and Ireland is generally above 90%, with high‐risk histology as the most important adverse prognostic factor. However, median tumour volume at diagnosis and after pre‐operative chemotherapy remains large.

A paradigm of childhood cancers is that they have a low mutation burden, with some ostensibly bearing fewer mutations than the normal tissues from which they derive. We set out to resolve this paradox by examining paediatric renal cancers with exceptionally few mutations using high resolution, high depth sequencing approaches. We find that apparent hypomutation is the result of unusual clonal architecture due to a normal tissue-like mode of tumour evolution, raising the possibility that the mutation burden of some cancers has been systematically misjudged.

Contains Supplementary Figures 1-9. Supplementary Figure 1 shows age of diagnosis of children and indel burden and rearrangement burden for tumours from predisposed children versus those with sporadic disease. Supplementary Figure 2 shows genomic evidence for novel predispositions. Supplementary Figure 3 shows global methylation patterns. Supplementary Figure 4 shows differential gene expression. Supplementary Figure 5 shows mutational signatures. Supplementary Figure 6 shows histological subtypes across predispositions and across somatic drivers. Supplementary Figure 7 shows polyclonal versus clonal enrichment of 11p LOH in normal kidneys. Supplementary Figure 8 shows phylogenies in children with multiple neoplasms and either WT1 or TRIM28 predispositions. Supplementary Figure 9 shows phylogenies in children with non WT1/ non TRIM28 predispositions or sporadic disease.

Contains Supplementary Tables 1-8. Supplementary Table 1 shows characteristics of discovery cohort. Supplementary Table 2 shows genes included in predisposition analysis. Supplementary Table 3 shows evidence underlying novel predispositions. Supplementary Table 4 shows variants that would be detectable by current clinical assays. Supplementary Table 5 shows substitutions and indels. Supplementary Table 6 shows rearrangements. Supplementary Table 7 shows 10,000 most variable probes. Supplementary Table 8 shows differentially expressed genes.

Approximately 20% of paediatric and adolescent/young adult patients with renal tumours are diagnosed with non-Wilms tumour, a broad heterogeneous group of tumours that includes clear-cell sarcoma of the kidney, congenital mesoblastic nephroma, malignant rhabdoid tumour of the kidney, renal-cell carcinoma, renal medullary carcinoma and other rare histologies. The differential diagnosis of these tumours dates back many decades, when these pathologies were identified initially through clinicopathological observation of entities with outcomes that diverged from Wilms tumour, corroborated with immunohistochemistry and molecular cytogenetics and, subsequently, through next-generation sequencing. These advances enabled near-definitive recognition of different tumours and risk stratification of patients. In parallel, the generation of new renal-tumour models of some of these pathologies including cell lines, organoids, xenografts and genetically engineered mouse models improved our understanding of the development of these tumours and have facilitated the identification of new therapeutic targets. Despite these many achievements, paediatric and adolescent/young adult patients continue to die from such rare cancers at higher rates than patients with Wilms tumour. Thus, international coordinated efforts are needed to answer unresolved questions and improve outcomes.