Download This Paper
Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.
Causal Germline Variants in Children with Cancer
33 Pages Posted: 15 Jul 2024
More...Abstract
Background: Cancer predisposition syndromes (CPSs) are the leading known cause of childhood malignancies and are increasingly guiding clinical precision prevention strategies in pediatric oncology. However, reported rate of CPSs in pediatric pancancer studies vary greatly from 4 to 18%.
Method: In a 5-year prospective, registry-validated, nationwide cohort, as well as a separate retrospective cohort, we performed whole-genome sequencing (WGS) of germline DNA from Danish individuals diagnosed with cancer before 18 years of age. Pathogenic variants were assessed for genotype-phenotype matches. Additionally, we compared the burden of private germline variants in our study to those observed in 125,748 gnomAD exomes.
Results: Across a total of 1,127 participants, 16% carried a pathogenic variant in at least one CPS gene, yet, only half of these genotypes matched the observed cancer. Thus, 9% of children in the prospective cohort (n=651) carried a variant considered causative, a rate deemed significantly higher than previous studies (RR = 0.65, 95%CI 0.57 - 0.73, p = 1e-14) — with variants in NF1 and ETV6 as well as trisomy 21, being significantly underrepresented in the literature, and variants in TP53 being overrepresented. As predicted for a disease cohort subject to negative Darwinian selective pressure, we found a significant excess of predicted loss-of-function (pLoF) variants in the 1,500 most mutationaly constrained genes. Surprisingly, this excess was three times greater than expected, leaving a significant residual enrichment of pLoF variants in genes evolutionarily considered the least tolerant to damage (RR = 1.41, 99%CI 1.09 - 1.80, p = 4e-4).
Conclusion: The high frequency of CPS, many apparently still uncharted, emphasizes the need for systematic and extensive germline genomic mapping as part of the diagnostic work-up of childhood cancer patients and linkage of such data to disease and response phenotypes to guide future pediatric oncological care.
Funding: The European Union Interregional Program ØKS; Danish Cancer Society, R-257- A14720, Danish Childhood Cancer Foundation, 2019-5934 XXX+++XXX, Novo Nordisk Foundation (NNF21SA0072102, NNF23SA0084103).
Declaration of Interest: None to declare.
Ethical Approval: Studies investigating cohorts P and S were jointly approved by Danish ethical authorities in the tracking number H-15016782. The study investigating cohort N was approved separately by the National Ethical Committee with the tracking number NVK2000407.
Keywords: predisposition, pediatrics, evolution, genomics, next-generation sequencing, mutational constraint, clinical genetics
Suggested Citation: Suggested Citation