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Developmental origins shape the paediatric cancer genome

Nature Reviews Cancer (2024)Cite this article

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Abstract

In the past two decades, technological advances have brought unprecedented insights into the paediatric cancer genome revealing characteristics distinct from those of adult cancer. Originating from developing tissues, paediatric cancers generally have low mutation burden and are driven by variants that disrupt the transcriptional activity, chromatin state, non-coding cis-regulatory regions and other biological functions. Within each tumour, there are multiple populations of cells with varying states, and the lineages of some can be tracked to their fetal origins. Genome-wide genetic screening has identified vulnerabilities associated with both the cell of origin and transcription deregulation in paediatric cancer, which have become a valuable resource for designing new therapeutic approaches including those for small molecules, immunotherapy and targeted protein degradation. In this Review, we present recent findings on these facets of paediatric cancer from a pan-cancer perspective and provide an outlook on future investigations.

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Fig. 1: The spectrum and drivers of paediatric cancers.
Fig. 2: Chromatin modifiers disrupted in paediatric cancer.
Fig. 3: Mechanisms of cis-activation of proto-oncogene in paediatric cancers.
Fig. 4: A new hypothesis for the acquisition of cancer hallmarks in paediatric cancer.

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Acknowledgements

The authors thank K. Stegmaier, A. Durban, J. J. Yang and Z. Rankovic for help in reviewing the content of Table 1. They thank P. Geeleher, A. Durban, L. Helman, S. J. Baker, D. A. Wheeler, J. Yu, X. Chen, T. Look, J. Maris, M. Dyer, S. Brady and V. Pastor Loyola for critical feedback on the manuscript. L. Robison provided the Surveillance, Epidemiology, and End Results Program (SEER Program) data for calculating the distribution of cancer types. An early discussion with R. Weinberg  and X. Ma inspired our interest in comparing the differences between paediatric and adult cancers. M. Edmonson helped proofread the manuscript. This study was supported, in part, by National Cancer Institute (NCI) grants R01CA216391 to J.Z. and R01CA113794, R01CA172152 and R01CA273455 to C.W.M.R., and by a Cancer Center Support Grant (P30 CA21765) to C.W.M.R. The study is also supported by American Lebanese Syrian Associated Charities (ALSAC), the St. Jude Research Collaborative Consortium of the 3D Genome and the Chromatin Collaborative.

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Authors and Affiliations

  1. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Xiaolong Chen, Wentao Yang & Jinghui Zhang

  2. Comprehensive Cancer Center, St Jude Children’s Research Hospital, Memphis, TN, USA

    Charles W. M. Roberts

  3. Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Charles W. M. Roberts

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  1. Xiaolong Chen
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Contributions

J.Z. conceived the manuscript. J.Z., X.C. and C.W.M.R. wrote the manuscript. X.C. and W.Y. summarized the data and generated the figures.

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Correspondence to Jinghui Zhang.

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C.W.M.R. is a scientific advisory board member of Exo Therapeutics, unrelated to this manuscript. The other authors declare no competing interests.

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Related links

American Childhood Cancer Organization: https://www.acco.org/us-childhood-cancer-statistics/

Catalogue Of Somatic Mutations In Cancer (COSMIC): https://cancer.sanger.ac.uk/cosmic

DepMap Portal: https://depmap.org/portal

SEER Program: https://seer.cancer.gov

St. Jude Cloud Paediatric Cancer Knowledge (PeCan): https://pecan.stjude.org/

The Paediatric Cancer Dependencies Accelerator: https://peddep.org

Supplementary information

Glossary

Adrenergic state

The adrenergic state in neuroblastoma refers to a differentiated cell identity similar to sympathetic neurons, characterized by the expression of genes for adrenaline production.

Aflatoxin

A member of a family of toxins produced by certain fungi that are found on agricultural crops such as maize (corn), peanuts, cottonseed and tree nuts. Exposure to aflatoxin is associated with increased risk of hepatocellular carcinomas.

Chromaffin cells

Cells found in the adrenal medulla that release adrenaline and noradrenaline can be involved in the development of neuroblastoma, contributing to its characteristic symptoms and biological behaviour.

Chromatin modifiers

Enzymes or proteins that add or remove post-translational modification to or from DNA and histones, affecting chromatin structure and gene expression.

Chromatin remodellers

Complexes that reposition, slide, evict or alter the structure of nucleosomes/histone/histone variants, thereby changing the accessibility of chromatin to regulate gene expression.

Clonal haematopoiesis

A condition where blood cells originating from a single haematopoietic stem cell with a specific genetic mutation proliferate more than other cells, creating a population of blood cells with a distinct genetic pattern.

Core regulatory circuitry

A network of transcription factors that regulate the key genes defining cell identity and function.

Ectodermal lineage

Cells that derive from the ectoderm, the outermost germ layer of the embryo, developing into structures such as skin and nervous tissue.

Ependymoma

A rare tumour originating from ependymal cells lining the ventricles and passageways of the brain and spinal cord, characterized by the uncontrolled growth of these cells that produce cerebrospinal fluid.

Epipodophyllotoxins

A class of chemotherapeutic agents derived from the podophyllotoxin that inhibit DNA topoisomerase II, leading to DNA damage and cell death.

Genetic dependency screening

Loss-of-function screening using RNA interference or CRISPR approaches to identify genes that specific cancer cell lines depend upon for survival.

GGAA repeat microsatellites

In Ewing sarcoma, GGAA repeat microsatellites serve as binding sites for the Ewing sarcoma breakpoint region 1 (EWSR1)–friend leukaemia virus integration 1 (FLI1) fusion protein (EWS-FLI), a consequence of chromosomal translocation, enabling the aberrant regulation of gene expression critical to tumour development.

Group 3 medulloblastoma

This highly aggressive and metastatic subtype is known for MYC amplification and a poor prognosis, particularly affecting young children, and is characterized by various genetic alterations.

Group 4 medulloblastoma

The most common subtype, exhibiting a wide range of genetic alterations including isochromosome 17q and showing variable prognosis, with certain chromosomal gains and losses indicating a more favourable outcome.

Hot L1 element

A particularly active LINE-1 (L1) element that is capable of frequent transposition and often contributes to genetic diversity and diseases.

Hyperdiploidy

A major subtype of paediatric B-lineage acute lymphoid leukaemia (B-ALL) that is traditionally diagnosed with chromosome copy number abnormalities with chromosome counts between 52 and 67 in different studies.

Hypermutator phenotype

A cellular state characterized by an abnormally high mutation rate, with the tumour mutational burden exceeding ten mutations per megabase, often due to defects in DNA mismatch repair (MMR).

Immune checkpoint inhibitors

Drugs that block certain proteins which regulate immune responses, thereby enhancing the ability of T cells to attack cancer cells, commonly targeting checkpoint proteins such as PD-1 or PD-L1.

Insulated neighbourhoods

Chromosomal loop structures formed by the interaction of two DNA sites bound by the CCCTC binding factor (CTCF) protein and occupied by the cohesin complex.

LINE-1 (L1) element

A family of related class I transposable elements classified with the long interspersed elements (LINEs) that comprise 17% of human DNA; active retrotransposons can alter gene function and influence genome stability, thereby contributing to cancer.

Medulloblastoma

A tumour that arises in the cerebellum, part of the brain located at the base of the skull. Medulloblastoma is the most common cancerous brain tumour in children and is subdivided into four main subgroups (WNT, SHH, group 3 and group 4) based on their distinct demographic, transcriptional, genetic and clinical features.

Mesodermal lineage

Cells that originate from the mesoderm, one of the three primary germ layers in early embryonic development, which give rise to tissues such as muscle, bone and blood.

Molecular glues

Small molecules that facilitate the interaction between two protein surfaces, enhancing their affinity for each other and often inducing novel protein–protein associations, potentially altering protein function for therapeutic purposes.

Multimodal single-cell assays

Assays that integrate multiple types of single-cell data (for example, transcriptomic, epigenomic, proteomic) from the same cell, providing a holistic view of cellular function.

Neuroblast

The large cell in the early embryo, from which the nervous system develops.

Neuroblastoma

A paediatric cancer originating from immature nerve tissue, predominantly in the adrenal glands atop the kidneys.

Neuronal-like populations

Cells or groups of cells that exhibit characteristics similar to neurons.

Perturb-seq

A technique combining CRISPR-based perturbations with single-cell RNA sequencing to study gene function.

Pharmacotyping

A comprehensive analysis of drug sensitivity across molecularly defined cancer subtypes to understand and predict treatment responses, thereby guiding precision medicine tailored to individual patient profiles.

Posterior fossa group A

Ependymomas that primarily occur in infants and young children, which arise from the lateral recess of the fourth ventricle and exhibit few mutations and distinct chromosomal changes such as gain of chromosome 1q and loss of 6q, marked by the loss of trimethylated histone H3 K27, often due to EZH inhibitory protein (EZHIP) mutations or overexpression and, sometimes, K27M mutations in H3.

Primitive vesicle cells

As forerunners in kidney organogenesis, primitive vesicle cells can, through oncogenic mutations, lead to kidney tumours by disrupting the normal development of nephrons, the kidney’s filtration units.

Proteolysis targeting chimera

(PROTAC). A chemical strategy in which a small molecule that binds to a protein of interest is joined by a linker, bridged to an immunomodulatory drug that interacts with an E3 ubiquitin ligase receptor (for example, von Hippel–Lindau (VHL) or cereblon), so that the protein of interest is juxtaposed to the E3 ligase resulting in its polyubiquitination followed by proteasomal degradation.

Rhabdomyosarcoma

A malignant soft tissue tumour made up of cells that normally develop into skeletal muscles. Rhabdomyosarcoma is characterized by four histological subtypes, including embryonal, alveolar, spindle cell/sclerosing and pleomorphic, with distinct genomic profiles — embryonal types often showing loss of heterozygosity at 11p15 and RAS pathway mutations, and alveolar types characterized by FOXO1 fusions with paired box 3 (PAX3) or PAX7.

Rhombic lip

An embryonic structure in the hindbrain that acts as a source of neuronal precursors, implicated in the tumour’s developmental origin, especially in medulloblastoma.

SHH medulloblastoma

Characterized by activation of the Sonic Hedgehog pathway, this subtype shows variability in prognosis depending on TP53 mutation status and is characterized by chromosome 9q deletions, desmoplastic/nodular histology and mutations in SHH-pathway genes.

Single-cell epigenomics

A technique that focuses on analysing epigenetic modifications, such as DNA methylation and histone modifications, at the single-cell level enabling the elucidation of heterogeneity in epigenetic states across individual cells.

Small round cell sarcoma

A small round cell tumour that encompasses a group of undifferentiated sarcomas of bone and soft tissue, including Ewing sarcoma, distinguished historically by the small, round, blue-cell morphology under light microscopy.

Spatial transcriptomics

A technique that maps the gene expression profiles of tissues in a spatially resolved manner, highlighting the spatial heterogeneity of cellular processes.

Sympathetic differentiation state

A developmental phase where neural crest-derived progenitors progress towards becoming mature sympathetic neurons.

Temozolomide

An oral chemotherapy drug used to treat certain types of tumours. It is an alkylating agent delivering a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, can be removed by methylguanine methyltransferase (MGMT) or tolerated in mismatch repair (MMR)-deficient tumours, both of which can lead to drug resistance.

Topologically associating domains

(TADs). The regions with relatively high intradomain DNA interaction frequencies as measured by Hi-C chromosome conformation capture data that form 3D structural units of the genome constraining the interactions between regulatory DNA elements, such as enhancers and promoters and their target genes.

Ultraviolet-light mutational signature

A distinct pattern of genomic mutations, predominantly characterized by pyrimidine–pyrimidine photodimers, which is indicative of damage caused by ultraviolet radiation.

Ureteric bud

An embryonic structure that forms the drainage system of the kidney, and anomalies in its development are implicated in the aetiology of Wilms’ tumour.

Wilms tumour

The most common renal cancer in infants and children, with an incidence of 10.4 cases per million children aged younger than 15 years, featuring a slightly higher occurrence in unilateral than bilateral cases, and associated with various congenital malformation syndromes in about 10% of cases.

WNT medulloblastoma

Identified by activation of the WNT signalling pathway predominantly caused by mutations in the gene catenin-β1 (CTNNB1), this subtype is associated with the best prognosis among all medulloblastoma subtypes.

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Chen, X., Yang, W., Roberts, C.W.M. et al. Developmental origins shape the paediatric cancer genome. Nat Rev Cancer (2024). https://doi.org/10.1038/s41568-024-00684-9

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