The developmental roots of childhood cancer: genomic insights from Wilms tumor and single-cell sequencing

In this Royal Society lecture, Sam Bahati explains how childhood cancers originate during human development, not later in life. He traces the journey from Sydney Farber's early chemotherapy to modern genomics, where reading the genome has become fast and affordable. Bahati emphasizes that despite advances, about 20% of children are not cured and survivors face late effects. The talk introduces the idea that cancers can arise from developmental roots or fields in tissue, as shown in Wilms tumor, where cancer mutations can be found in adjacent normal kidney. Using single-cell RNA sequencing and the concept of developmental barcodes, his team reconstructs cancer lineage and highlights hypermethylation of the H19 gene as a key mechanism. The future may include urine screening for cancer roots and prenatal strategies to prevent cancer development.

Overview and Significance

The talk centers on how childhood cancers originate in development, contrasting this with adult cancers that accumulate mutations over time. Bahati reviews the dramatic gains in cure rates through chemotherapy but notes that about one in five children are not cured and late effects remain a concern. He frames cancer as a disease of mutations and explains how the genome project has transformed our understanding of cancer biology, enabling a shift from viewing cancer as a single seed to recognizing complex developmental processes that seed cancer across tissues.

From Genomes to Cancer: The Sequencing Revolution

The lecture traces the arc from Sanger sequencing to today’s rapid genome reading, highlighting a shift from the Human Genome Project era, which took 13 years and cost billions, to modern technologies that read entire genomes in days or hours on compact chips. Bahati emphasizes that sequencing not only reveals the letters of DNA but also enables us to read the cellular programs driven by RNA, which tell cells what to do. This technological leap underpins the search for cancer origins in childhood and informs strategies for prevention and early detection.

Childhood Cancer Origins: Development, Mutations, and Challenges

Bahati explains that childhood cancers like Wilms tumor arise during development, when cells are rapidly growing and differentiating. Mutations can occur during DNA replication or due to environmental exposures, but the developmental timing means the origin of childhood cancers is fundamentally tied to embryology and organogenesis. In contrast, most adult cancers accumulate mutations over a lifetime. Because development is a black box in humans, researchers must devise strategies to infer origins without direct developmental experimentation in humans, using human-derived data and computational approaches.

The Human Cell Atlas and Wilms Tumor Experiments

The Human Cell Atlas, a landmark project using single-cell RNA sequencing, provides high-resolution maps of cell types in normal and developing tissues. Bahati describes applying this framework to Wilms tumor, a childhood kidney cancer that also yields normal kidney tissue for comparison. The goal is to understand which normal cell types are most related to the tumor and to reconstruct the lineage relationships that lead from normal development to cancer, rather than assuming a simple seed-based origin.

Cancer Roots, Fields, and the Hyper-methylation Mechanism

In a pivotal finding, the team observed cancer mutations in normal-appearing kidney tissue, suggesting a cancer root or field rather than a single initiating cell. Across multiple cases and through deep sequencing, they found that many tissues contained a hypermethylation change at the H19 gene, which acts as a brake on cell growth. The loss of this brake could create a permissive field for tumor formation. This discovery points to a broader concept: cancer predisposition may be driven by developmental epigenetic changes that prime tissues for later cancer development, offering new angles for risk assessment and prevention.

Predisposition and Early Embryonic Mutations: The NF1 Example

The talk moves to cancer predisposition, noting that roughly 10% of children with cancer carry a germline predisposition. A deep dive into neurofibromatosis type 1 (NF1) revealed that in affected children, the second copy of NF1 is frequently mutated in normal-looking tissues, including large tissue blocks rather than isolated cells. These early embryonic mutations can spread to various brain regions, showing how developmental timing and spatial distribution influence cancer risk. This work suggests measurable patterns that could someday inform screening and prevention strategies for predisposed children.

Future Directions: Screening, Prevention, and Epigenetics

Looking forward, Bahati discusses possibilities for detecting cancer roots at birth using urine assays to detect kidney roots before tumors form, followed by targeted ultrasound monitoring. He also draws a cautious parallel with folic acid prevention of neural tube defects, suggesting that understanding cancer root biochemistry might enable preventive interventions, including dietary or metabolic approaches during pregnancy. He emphasizes epigenetics as a dynamic and rapidly evolving field that will shape our understanding of developmental predisposition and cancer risk, while acknowledging debates around newborn genome screening and penetrance, which require careful evidence and policy debate.

Global Collaboration, Ethics, and the Human Face of Science

The presentation highlights the UK Umbrella Study and international collaborations that enable systematic tumor and normal-tissue sampling across units. Bahati pays tribute to families and clinicians who contribute tissues and data, underscoring the human dimension of pediatric cancer research. He closes by acknowledging the complexity of cancer, the importance of focusing on the cancer cell biology, and the promise of integrating genetics, epigenetics, and single-cell technologies to transform prevention and early detection in childhood cancer.

Conclusion

Bahati frames the journey as a move from treatment to prevention through understanding the developmental roots of cancer. By mapping cancer origins at the single-cell level, detecting epigenetic signatures, and exploring early screening possibilities, the field moves toward a future where childhood cancer can be prevented or detected long before it manifests clinically, reducing burden for patients, families, and healthcare systems.