Genome-wide association studies reveal novel locus with sex-/therapy-specific fracture risk effects in childhood cancer survivors

Abstract

Survivors of childhood cancer treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, research focusing on how genetic and clinical susceptibility factors jointly contribute to fracture risk among long-term ([≥]5 years) survivors of childhood cancer has been limited. To address this gap, we conducted genome-wide association studies of fracture risk in 2,453 participants from the Childhood Cancer Survivor Study (CCSS) using Cox regression models and prioritized sex- and treatment-stratified genetic associations. Replication analyses were conducted in an independent survivor sample from the St. Jude Lifetime Cohort Study (SJLIFE). We identified a genome-wide significant (P36 Gray). In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways, and are plausibly moderated by head/neck RT. Genetic risk profiles integrating this locus may help identify young female survivors who would benefit from targeted interventions to reduce fracture risk.