Molecular characteristics and therapeutic vulnerabilities across paediatric solid tumours


The spectrum of tumours arising in childhood is fundamentally different from that seen in adults, and they are known to be divergent from adult malignancies in terms of cellular origins, epidemiology, genetic complexity, driver mutations and underlying mutational processes. Despite the immense knowledge generated through sequencing efforts and functional characterization of identified (epi-)genetic alterations over the past decade, the clinical implications of this knowledge have so far been limited. Novel preclinical platforms such as the European Innovative Therapies for Children with Cancer–Paediatric Preclinical Proof-of-Concept Platform and the US-based Pediatric Preclinical Testing Consortium are being developed to try to change this by aiming to recapitulate the extensive heterogeneity of paediatric tumours and thereby, hopefully, improve the ability to predict clinical benefit. Numerous studies have also been established worldwide to provide patients with access to real-time molecular profiling and the possibility of more precise mechanism-of-action-based treatments. In addition to tumour-intrinsic findings and mechanisms, ongoing studies are investigating features such as the immune microenvironment of paediatric tumours in comparison with adult cancers — currently of very timely clinical relevance. However, there is an ongoing need for rigorous preclinical biomarker and target validation to feed into the next generation of molecularly stratified clinical trials. This Review aims to provide a comprehensive state-of-the-art overview of the molecular landscape of paediatric solid tumours, including their underlying genomic alterations and interactions with the microenvironment, complemented with our current understanding of potential therapeutic vulnerabilities and how these can be preclinically tested using more accurate predictive methods. Finally, we provide an outlook on the challenges and opportunities associated with translating this overwhelming scientific progress into real clinical benefit.

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Fig. 1: Immunotherapy approaches for paediatric solid malignancies.
Fig. 2: Overview of national and international precision medicine programmes for paediatric oncology.


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The authors acknowledge the valuable contribution from E. Mould and V. Tyrrell to the design of figure 2 and manuscript content. We also thank all those contributing to the personalized medicine programmes listed as well as the patients and their families, who have made the advances outlined here possible by consenting to take part in scientific and/or clinical studies.

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D.T.W.J., A.B., T.G.P.G., M.H., N.J., M.K., T.M., J.J.M., A.N., T.J.P., G.S., M.A.S., F.W. and S.M.P. researched the content for the article, discussed and prepared the text and display items, and approved the final manuscript.

Correspondence to Stefan M. Pfister.

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Nature Reviews Cancer thanks N. Gottardo, K. Stegmaier and M. Roussel for their contribution to the peer review of this work.

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Radial glia cells

Ventricular zone progenitor cells characterized by long radial processes that support neuron formation and migration.


Referring to a brain region located in the area above the tentorium cerebelli that contains the cerebral hemispheres along with the basal ganglia, thalamus and other midline structures.

Posterior fossa

Also known as the infratentorial region. A brain region located in the area below the tentorium cerebelli that contains the cerebellum and brain stem.

Embryonal tumours

Tumours originating from embryonic (fetal) tissue.

SWI/SNF complex

Multiprotein complex responsible for nucleosome remodelling.

Uniparental disomy

A type of copy-neutral structural variation, characterized as the same-parent origin of both chromosomes of a homologous chromosome pair.

Telomere maintenance mechanisms

(TMMs). To avoid critical telomere shortening due to successive cell divisions, tumour cells can adopt telomere maintenance mechanisms either by reactivation of the telomerase enzyme or by the telomerase-independent, recombination-mediated alternative lengthening of telomeres (ALT) pathway.

Risk-adapted therapy

Strategy consisting of specific treatment protocols based on individual risk stratification and designed to increase the likelihood of cure while minimizing late therapy-related effects.

Pilocytic astrocytoma

A World Health Organization (WHO) Grade I tumour thought to be of astrocytic origin, primarily arising during childhood and typically driven by alterations of the MAPK signalling pathway. ‘Pilocytic’ refers to the elongated, hair-like (piloid) processes that often characterize the tumour cells.


A family of small molecules identified from a high-throughput screen that inhibit the interaction between MDM2 and p53, with the aim of re-activating p53 function in cells where wild-type p53 is inhibited by elevated MDM2 levels.

Replication stress

A process occurring typically during DNA replication when the genome is exposed to one of a number of stressful stimuli, which can result in stalled replication forks and other errors in the cell cycle.

Neurological sequelae

Long-term complications of central nervous system disease, which can affect cognitive, sensory and motor functions, thereby negatively impacting the quality of life of a patient long after the original disease process is cured.

Antibody–drug conjugate

Complex molecule composed of a monoclonal antibody linked to a biologically active cytotoxic anticancer agent.


A combination of pharmacology and genomics, this relatively new field investigates how variants in genes involved in different aspects of drug processing can affect an individual’s response to a given therapy.

Pharmacokinetic profile

A description of how the processes of absorption and distribution, as well as metabolic processing and excretion, affect the levels of a drug present within the body in the period after its administration.

T cell bispecific antibodies

Antibodies that can simultaneously bind to CD3ε, a component of the T cell receptor complex, and to a tumour antigen, enabling the formation of an immunological synapse between the tumour cell and the T cell that results in tumour killing.

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