Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia

Abstract

Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetics of osteonecrosis have focused on patients ≥10 years of age, leaving the genetic risk factors for the larger group of children <10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children <10 years. The discovery cohort comprised 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) standard-risk ALL protocol AALL0331 (NCT00103285, https://ichgcp.net/clinical-trials-registry/NCT00103285), with results tested for replication in 817 children <10 years treated on COG protocol AALL0232 (NCT00075725, https://ichgcp.net/clinical-trials-registry/NCT00075725). The top replicated single nucleotide polymorphisms (SNPs) were near bone morphogenic protein 7 [BMP7: rs75161997, P = 5.34 × 10(-8) (odds ratio [OR] 15.0) and P = .0498 (OR 8.44) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 (PROX1-AS1: rs1891059, P = 2.28 × 10(-7) [OR 6.48] and P = .0077 [OR 3.78] for the discovery and replication cohorts, respectively). The top replicated nonsynonymous SNP, rs34144324, was in a glutamate receptor gene (GRID2, P = 8.65 × 10(-6) [OR 3.46] and P = .0136 [OR 10.8] in the discovery and replication cohorts, respectively). In a meta-analysis, the BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the significance threshold of <5 × 10(-8). Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and analysis of annotated genes demonstrated enrichment in glutamate receptor and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis.

© 2016 by The American Society of Hematology.

Figures

Figure 1

Consort diagram of 369 patients in discovery cohort treated on AALL0331.

Figure 2

Cumulative incidence of osteonecrosis in the discovery cohort based on genotype for top BMP7 variants. All 5 patients in the discovery cohort (82 cases, 287 controls) carrying variant alleles of 2 SNPs in high LD (rs77556622 [T>C], rs76599360 [C>T]; P = 1.13 × 10−9) located 3′ to BMP7 developed osteonecrosis. Patient age, ancestry, sex, and therapy group are shown next to each case of osteonecrosis in the variant allele group. Therapy groups are defined in the supplemental Materials, with group 1 receiving the most intense therapy and group 4 receiving the least intense.

Figure 3

Manhattan plot of meta-analysis for osteonecrosis in patients 1 to 10 years of age. SNPs (N = 9157) with associations with osteonecrosis (P < .05) in both the discovery and replication cohorts are shown in red or orange. The top coding SNP (rs34144324 in GRID2, meta-analysis P = 7.07 × 10−7) and loci reaching genome-wide significance (PROX1-AS1, rs1891059, P = 8.72 × 10−9; LINC00251, rs141059755, P = 1.30 × 10−8; BMP7, rs79085477 and rs75161997, P = 8.29 × 10−9) are noted.