Genetic susceptibility and late bone outcomes in childhood acute lymphoblastic leukemia survivors

Abstract

Abstract Childhood acute lymphoblastic leukemia (cALL) survivors are at increased risk for bone comorbidities, but accurate screening tools for such comorbidities are limited. Polygenic scores (PGS) could stratify cALL survivors for risk of long–term adverse bone outcomes. We evaluated 214 (51% female) cALL survivors from the Prévenir les Effets TArdifs de la LEucémie study (median age 21 yr). Bone mineral density (BMD) measurements were obtained using dual X–ray absorptiometry at the lumbar spine (LS-BMD), femoral neck (FN-BMD), and total body (TB-BMD), and vertebral fractures (VF) were documented using the vertebral deformity criterion. We computed a PGS for adult heel quantitative ultrasound speed of sound (gSOS), known to be associated with the risk of osteoporotic fracture, using imputed genotype data of the participants, and tested it for association with BMD Z-scores and VF risk, adjusting for clinical risk factors, and in sex and prognostic risk-stratified analyses. We found that a gSOS below the mean was associated with lower BMD in all three sites in univariate and multivariate models. In univariate analyses, 1 SD increase in gSOS conferred a 0.16 SD increase in LS-BMD (95% CI 0.005-0.31), whereas a gSOS above the mean was associated with a 0.31 SD higher LS-BMD (95% CI 0.008-0.61), a 0.36 SD higher TB-BMD (95% CI 0.06-0.67), and a 0.43 SD higher FN-BMD (95% CI 0.13-0.72). Models combining gSOS with clinical risk factors explained up to 16% of the variance of BMD phenotypes and obtained an area under the receiver operating characteristic curve for VF of 0.77 in subgroup analyses. Cranial radiation, high cumulative glucocorticoid doses, high risk group, and male sex were significant risk factors for lower BMD Z-scores. In conclusion, a PGS, in combination with clinical risk factors, could be used as a tool to risk stratify cALL survivors for treatment–related bone morbidity.