Objectives: Survivors of childhood acute lymphoblastic leukemia (cALL) present elevated fracture rates compared to the general population. A polygenic risk score for estimated bone mineral density (BMD), named gSOS, validated to predict the risk of adult osteoporotic fracture, has been previously associated with significant fracture risk in childhood. We hypothesized that gSOS could be associated with long-term, bone health-related mobidities in survivors of cALL.
Methods/Results: We recruited 245 (50.6% female) long-term cALL survivors, treated from 1987 to 2005 (PETALE cohort). Median age at recruitment was 21.7y (range 8.5 – 41y) and median time since diagnosis was 15.1y (range 5.4 – 28.2y). For all participants, BMD measures (Z-scores) were obtained using Dual-energy X-ray absorptiometry (DEXA) at the lumbar spine (LS-BMD), femoral neck (FN-BMD) and total body (TB-BMD), and vertebral fractures since cALL diagnosis were documented (Ntotal with vertebral fracture (yes/no)=57). We computed gSOS measures in 220 PETALE participants (107 males, 113 females) with available imputed genotype data. gSOS was standardized (mean=0, SD=1) and tested for association with the three BMD Z-score measurements and vertebral fracture risk. Multivariate analyses adjusted for age at the time of BMD evaluation, sex, cumulative corticosteroid dose, cranial irradiation, fitness, and age at diagnosis. We also performed sex- and relapse risk group-stratified analyses. gSOS was significantly associated with LS-BMD (β=0.15, 95% CI= 0.13-0.18 P=0.04) in both sexes. In sex-stratified analyses, this association was only present in females (β=0.27, 95% CI=0.22-0.32, P=0.008). We did not observe significant effects of gSOS on FN-BMD, TB-BMD, and vertebral fracture risk, but we had limited power to study the latter associations. Notably, risk group stratification did not unravel differences in the association of gSOS with the studied outcomes between standard and high-risk groups.
Conclusion: Our findings are a step towards using polygenic risk scores to predict bone health outcomes in survivors of childhood cancer. This could allow for targeted screening of cALL survivors who are at the highest risk of treatment-related musculoskeletal late effects, and for optimized allocation of health resources. We are applying a similar approach to assess effects of polygenic predictors on long-term cardiometabolic and mental health oucomes in PETALE.
15 Sep 2022 - 17 Sep 2022