ArticleNeuro-oncology2023
Genetic predisposition and evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors.
Article in Neuro-oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 2 of them syntheses that pooled it.
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10 citing papers in PubMed, 2 syntheses or guidelines pooled it, 20 citations in OpenAlex.
- Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus.Neuro-oncology · 2023Pooled it
- Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort.Acta neuropathologica communications · 2022Pooled it
- Article
- Misclassification of a frequent variant from PMS2CL pseudogene as a PMS2 loss of function variant in Brazilian patients.Familial cancer · 2024Article
- Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach.Cancers · 2024Review
- Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors-a nationwide, prospective Swedish study.The Lancet regional health. Europe · 2024Article
- Beyond the WHO 2021 classification of the tumors of the central nervous system: transitioning from the 5th edition to the next.Brain tumor pathology · 2024Article
- The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification.Molecular genetics & genomic medicine · 2023Article
- Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.Journal of medical genetics · 2023Article
- Early-onset grade 2-3 diffuse gliomas and schwannomas increase the risk of central nervous system tumors among the patients' relatives.Neuro-oncology advancesArticle
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Authors and funding
16 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking.
methodsIn this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives.
resultsThirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e-4) and all other genes (P = 5e-17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity-raising the question of the role of other highly constrained gene alterations detected.
conclusionsApproximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.
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