Genetic predisposition is an important underlying cause of childhood cancer, although the proportion of patients with childhood cancer carrying predisposing pathogenic germline variants is uncertain. This review considers the pathogenic or likely pathogenic germline variants reported by six studies that used next-generation sequencing to investigate genetic predisposition in selected cohorts of patients with childhood cancer and used incompletely overlapping gene sets for analysis and interpretation. These six studies reported that 8.5%–35.5% of patients with childhood cancer carried clinically relevant germline variants. Analysis of 52 autosomal dominant cancer predisposition genes assumed common to all six studies showed that 5.5%–25.8% of patients with childhood cancer carried pathogenic or likely pathogenic germline variants in at least one of these genes. When only non-central nervous system solid tumours (excluding adrenocortical carcinomas) were considered, 8.5%–10.3% of the patients carried pathogenic or likely pathogenic germline variants in at least one of 52 autosomal dominant cancer predisposition genes. There was a lack of concordance between the genotype and phenotype in 33.3%–57.1% of the patients reported with pathogenic or likely pathogenic germline variants, most of which represented variants in autosomal dominant cancer predisposition genes associated with adult onset cancers. In summary, germline genetic testing in patients with childhood cancer requires clear definition of phenotypes and genes considered for interpretation, with potential to inform and broaden childhood cancer predisposition syndromes.
- paediatric oncology
- clinical genetics
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Contributors DES and JAB conceived the study; DES performed literature searches, all data analyses and wrote the original manuscript draft; JAB contributed to major revision of the manuscript; all authors reviewed and edited the manuscript.
Funding We gratefully acknowledge financial support from Australian Lions Childhood Cancer Research Fund (to DES), Cancer Institute NSW through the support of the Kids Cancer Alliance (to JAB and LD-P), Perpetual Foundation through the support of The Kids’ Cancer Project (to JAB and LD-P), Balance Foundation (to JAB and LD-P) and donations to the Children’s Cancer Research Unit.
Competing interests None declared.
Patient consent Not requried.
Provenance and peer review Not commissioned; externally peer reviewed.
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