TY - JOUR
T1 - Childhood Cancer Predisposition and Evolutionary Constraints
T2 - Novel Lessons from Germline Genomes from 1,127 Children with Cancer
AU - Stoltze, Ulrik Kristoffer
AU - van Overeem Hansen, Thomas
AU - Foss-Skiftesvik, Jon
AU - Byrjalsen, Anna
AU - Henriksen, Kasper Amund
AU - Laspiur, Adrian Otamendi
AU - Gerdes, Anne Marie
AU - Ostrowski, Sisse Rye
AU - Sørensen, Erik
AU - Bak, Mads
AU - Lautrup, Charlotte Kvist
AU - Grønskov, Karen
AU - Papaleo, Elena
AU - Hasle, Henrik
AU - Mikkelsen, Torben Stamm
AU - Wehner, Peder
AU - Saksager, Astrid Brix
AU - Andersen, Mette Klarskov
AU - Kjærsgaard, Mimi
AU - Hjortshøj, Tina Duelund
AU - Frederiksen, Jane Hübertz
AU - Scheie, David
AU - Olsen, Tina Elisabeth
AU - Tuckuviene, Ruta
AU - Olsen, Marianne
AU - Tümer, Zeynep
AU - Mathiasen, Rene
AU - Brok, Jesper
AU - Sehested, Astrid
AU - Gorissen, Bram L.
AU - Rasmussen, Simon
AU - Karczewski, Konrad J.
AU - Hjalgrim, Lisa L.
AU - Wadt, Karin A.W.
AU - Schmiegelow, Kjeld
N1 - Publisher Copyright:
© 2025 American Association for Cancer Research.
PY - 2025
Y1 - 2025
N2 - 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 ¼ 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 ¼ 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 ¼ 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 ¼ 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.
AB - 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 ¼ 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 ¼ 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 ¼ 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 ¼ 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.
U2 - 10.1158/1078-0432.CCR-25-0153
DO - 10.1158/1078-0432.CCR-25-0153
M3 - Journal article
C2 - 40815213
AN - SCOPUS:105020795254
SN - 1078-0432
VL - 31
SP - 4495
EP - 4509
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -
