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

Area of Science:

• Genomics
• Pediatric Oncology
• Evolutionary Biology

Background:

• Cancer predisposition syndromes (CPSs) are a major cause of childhood cancers and influence treatment strategies.
• Previous pediatric cancer studies have not fully utilized genomic evolutionary metrics to predict disease penetrance or identify new CPSs.

Purpose of the Study:

• To investigate the utility of genomic evolutionary metrics in predicting cancer predisposition syndrome penetrance.
• To identify novel cancer predisposition syndromes using an evolution-guided approach.

Main Methods:

• Germline whole-genome sequencing (WGS) was performed on a prospective cohort of children diagnosed with cancer before age 18.
• Evolution-guided burden analysis compared private germline variants in constrained genes against a large reference exome dataset (gnomAD).

Main Results:

• 16% of 1,127 participants carried a pathogenic variant in a CPS gene; 9% of 651 children had a causative variant, a significantly higher rate than previously reported.
• An excess of loss-of-function (LoF) variants was observed in constrained genes compared to reference adults, indicating negative Darwinian selective pressure.
• A significant residual enrichment of pLoF variants was found in genes evolutionarily least tolerant to damage, exceeding expectations.

Conclusions:

• The high prevalence of LoF variants in CPS genes underscores the necessity of routine germline genomic profiling for childhood cancer patients.
• Linking genomic data with clinical phenotypes is crucial for advancing pediatric oncology care and enabling pre-diagnostic interventions.