A groundbreaking study has shattered long-held assumptions about the genetic complexity of childhood cancers, revealing that some tumors harbor vastly more DNA alterations than previously recognized. This discovery fundamentally shifts our understanding of pediatric tumors and holds transformative potential for therapeutic strategies, including the repurposing of treatments traditionally reserved for adult cancers.
Focusing their investigation on Wilms tumor—a prevalent pediatric kidney cancer typically diagnosed in children under five—an international consortium of researchers employed cutting-edge genomic sequencing methodologies to profile tumors with unprecedented precision. This collaboration spanned leading institutions such as the Wellcome Sanger Institute, University of Cambridge, the Princess Máxima Center for Pediatric Oncology, the Oncode Institute in the Netherlands, Great Ormond Street Hospital, and Cambridge University Hospitals NHS Foundation Trust.
Traditional bulk whole genome sequencing methods characterize genetic variants shared across the entire tumor mass but often overlook mutations present only in smaller subpopulations of cells, particularly in rapidly developing pediatric tumors. These conventional techniques have contributed to the widely accepted notion that childhood cancers are genetically less complex than adult counterparts. To circumvent this limitation, the team integrated two innovative techniques: nanorate sequencing (nanoseq) and whole-genome sequencing of single-cell-derived organoids.
Nanorate sequencing enhances accuracy by independently tagging both strands of DNA, allowing the detection of even ultra-rare mutations with significantly reduced false positives. Meanwhile, sequencing of single-cell-derived organoids involves cultivating organoid structures originating from a solitary cancer cell. Sequencing these organoids provides a high-resolution snapshot of the genetic landscape within individual cancer cells, revealing mutations otherwise masked in bulk sequencing data.
Applying these methodologies to Wilms tumor samples from infants as young as six months, researchers uncovered that each cancer cell harbored an additional 72 to 111 unique genetic alterations beyond those detected by bulk sequencing. When extrapolated across the total cellularity of a tumor, this translates to millions of genetic changes per tumor—a staggering contrast to previous estimates ranging between 30 to 61 mutations per tumor.
The implications of this unexpectedly high mutational burden are profound. A diverse repertoire of mutations within a tumor can enable rapid evolution and adaptability, potentially increasing resistance to conventional therapies. Conversely, tumors with a greater number of mutations tend to respond more favorably to immunotherapies, treatments that harness the patient’s immune system to target cancerous cells. Until now, pediatric tumors were largely considered unsuitable candidates for such therapies due to presumed low mutational loads. This new evidence could reopen the door for personalized immunotherapeutic interventions in childhood cancers, revolutionizing treatment paradigms.
In a further breakthrough, the team traced tumor evolution in several cases, identifying a specific spontaneous mutation within the FOXR2 gene in a rare subtype of Wilms tumor present from birth. This mutation arises very early during fetal kidney development and is linked to unique histological features and RNA expression profiles. The identification of this genetic hallmark offers the tantalizing prospect of tailored diagnostics and individualized treatment regimens designed specifically for children harboring this mutation.
Dr. Henry Lee-Six from the Wellcome Sanger Institute highlighted the transformative potential of these findings: “These advanced sequencing technologies allow us to unravel the intricate genetic architecture of Wilms tumors at the single-cell level, revealing complexities that bulk methods masked. This deeper understanding could reshape how pediatric cancers are diagnosed and treated.” Dr. Jarno Drost of the Princess Máxima Center emphasized the clinical significance of such precision: “Understanding the genetic origins and evolution of these tumors equips us with crucial insights to design treatments that not only effectively target the cancer but also minimize collateral damage to young patients’ developing bodies.”
Professor Sam Behjati, also a senior author, remarked on the broader implications: “Our discovery challenges the entrenched belief that childhood tumors are genetically simple. It underscores that we have only been seeing the surface of their complexity. By fully deciphering these mutational landscapes, we open new avenues for repurposing adult cancer therapies for children, working toward faster access to effective treatments.”
Wilms tumor affects approximately 85 children annually in the UK alone, underscoring the pressing need for improved therapeutic options. The study’s revelations about the true scale of genetic mutations in these tumors signal a paradigm shift in pediatric oncology research and clinical practice. Enhanced genetic resolution provided by nanorate sequencing and single-cell organoid analysis represents a new frontier in understanding cancer heterogeneity and evolution from the earliest developmental stages.
This pioneering work also highlights the critical importance of interdisciplinary collaborations between genomic scientists, pediatric oncologists, and clinical researchers. By bridging technical innovation with clinical insight, the study paves the way for implementing more precise, mutation-informed strategies that could significantly enhance survival rates and quality of life for children afflicted with Wilms tumor and possibly other pediatric cancers.
As scientific tools continue to evolve, this research exemplifies the transformative impact of applying next-generation sequencing technologies to longstanding medical challenges. It provides an optimistic outlook for reimagining treatments for childhood cancers that were once considered genetically simple, now recognized as far more complex and potentially amenable to advanced therapeutic interventions.
Subject of Research: Genetic complexity and evolution of Wilms tumor in pediatric patients using advanced genomic sequencing techniques.
Article Title: High-resolution clonal architecture of hypomutated Wilms tumours
News Publication Date: 29-May-2025
Web References:
https://www.nature.com/articles/s41467-025-59854-4
References:
H. Lee-Six, T. D. Treger, M. Dave, et al. (2025). ‘High-resolution clonal architecture of hypomutated Wilms tumours’. Nature Communications. DOI: 10.1038/s41467-025-59854-4
Image Credits:
Ronald de Krijger / Princess Máxima Center for Pediatric Oncology
Keywords:
Cancer genetics, Cancer genomics, Cancer genome sequencing, Cancer patients, Pediatrics
