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. 2025 Nov 3;31(21):4495-4509.
doi: 10.1158/1078-0432.CCR-25-0153.

Childhood Cancer Predisposition and Evolutionary Constraints: Novel Lessons from Germline Genomes from 1,127 Children with Cancer

Ulrik Kristoffer Stoltze  1   2   3 , Thomas van Overeem Hansen  2   4 , Jon Foss-Skiftesvik  1   5 , Anna Byrjalsen  2 , Kasper Amund Henriksen  1   5 , Adrian Otamendi Laspiur  6 , Anne-Marie Gerdes  2 , Sisse Rye Ostrowski  4   7 , Erik Sørensen  7 , Mads Bak  2 , Charlotte Kvist Lautrup  8   9 , Karen Grønskov  2 , Elena Papaleo  6   10 , Henrik Hasle  11 , Torben Stamm Mikkelsen  11 , Peder Wehner  12 , Astrid Brix Saksager  1 , Mette Klarskov Andersen  2 , Mimi Kjærsgaard  1 , Tina Duelund Hjortshøj  2 , Jane Hübertz Frederiksen  2 , David Scheie  13 , Tina Elisabeth Olsen  13 , Ruta Tuckuviene  14 , Marianne Olsen  14 , Zeynep Tümer  2   4 , Rene Mathiasen  1 , Jesper Brok  1 , Astrid Sehested  1 , Bram L Gorissen  15   16 , Simon Rasmussen  15   17 , Konrad J Karczewski  3   15   16   18 , Lisa L Hjalgrim  1 , Karin A W Wadt  2   4 , Kjeld Schmiegelow  1   4
Affiliations

Childhood Cancer Predisposition and Evolutionary Constraints: Novel Lessons from Germline Genomes from 1,127 Children with Cancer

Ulrik Kristoffer Stoltze et al. Clin Cancer Res. .

Abstract

Purpose: Cancer predisposition syndromes (CPS) with pediatric onset are the leading known cause of childhood malignancies and are increasingly guiding clinical strategies in pediatric oncology. CPS are placed under evolutionary negative selective pressure, but pediatric pancancer studies have so far failed to investigate genomic evolutionary metrics as a guide to predict penetrance and reveal novel CPS.

Experimental design: Germline whole-genome sequencing was performed in a 5-year prospective, registry-validated, nationwide cohort of individuals diagnosed with cancer before age 18. Evolution-guided burden analysis of private germline variants in constrained genes was compared with 125,748 gnomAD exomes.

Results: Across a total of 1,127 participants, 16% carried a pathogenic variant in at least one CPS gene. After genotype-phenotype matching, 9% of children in the prospective cohort (n = 651) carried a variant considered causative, a rate deemed significantly higher than in previous studies [RR, 1.54, 95% confidence interval (CI), 1.37-1.75, P = 1 × 10-14]. As predicted for a disease subject to negative Darwinian selective pressure, compared with reference adults, we found a significant excess of loss-of-function (LoF) variants in the 1,500 most constrained genes (RR, 1.54, 99% CI, 1.21-1.95, P = 4 × 10-6). Surprisingly, this excess was greater than expected, leaving a significant residual enrichment of predicted LoF variants in genes evolutionarily considered the least tolerant to damage (RR, 1.41, 99% CI, 1.09-1.80, P = 4 × 10-4).

Conclusions: The high frequency of LoF variants, including in known CPS, emphasizes the need for systematic and extensive germline genomic mapping as part of the diagnostic workup of patients with childhood cancer and the linkage of such data to disease and response phenotypes to guide future pediatric oncological care and ultimately pave the way for prediagnostic interventional measures.

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