Four Pharmacogenomic Variants Strongly Linked to Corticosteroid-Induced Avascular Necrosis in Children with Cancer.

Abstract

Corticosteroids are effective anti-cancer agents for treating hematologic malignancies in children. However, avascular necrosis (AVN) is a common and debilitating adverse effect, leading to bone death and impacting long-term quality of life. This study aimed to uncover the genetic factors contributing to corticosteroid-induced AVN in a well-characterized cohort of pediatric cancer patients. We conducted a genome-wide association study (GWAS) on 972 patients, including 108 with AVN grade ≥2 and 864 dose-matched controls. The GWAS of 6.4 million genetic markers identified four significant AVN-associated loci (P < 5 × 10^-8): WNT7B (OR = 9.2; 95% CI, 3.8-22.0), POGK (OR = 8.4; 95% CI, 3.6-19.5), ZNF37A (OR = 6.0; 95% CI, 2.9-12.5), and a synonymous variant in FAM240C (OR = 5.0; 95% CI, 2.6-9.5). A multi-marker predictive model combining single nucleotide polymorphisms (SNPs) and clinical factors showed an area under the ROC curve (AUC) of 78.7%, outperforming SNP-only (67.8%) and clinical-only (68.4%) models. The osteogenic processes regulated by WNT7B, part of the Wnt signaling pathway, may contribute to AVN-related disrupted bone development and repair. Similarly, POGK and ZNF37A, both containing the KRAB domain, are hypothesized to affect osteoblast differentiation and skeletal development in AVN. Developing a predictive model for individual susceptibility to corticosteroid-induced AVN will enhance the monitoring and management of corticosteroid use in children with cancer.