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The Capital Region of Denmark - a part of Copenhagen University Hospital
E-pub ahead of print

Genetic predisposition & evolutionary traces of pediatric cancer risk: A prospective 5-year population-based genome sequencing study of children with CNS tumors

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BACKGROUND: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking.

METHODS: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3,543 close relatives.

RESULTS: Thirteen 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 2 986 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.

CONCLUSIONS: ∽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.

Original languageEnglish
JournalNeuro-Oncology
ISSN1522-8517
DOIs
Publication statusE-pub ahead of print - 29 Jul 2022

Bibliographical note

© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

ID: 79814532