This article is more than 5 years old. Information may no longer be current.
Researchers identify genetic osteonecrosis risk factors in pediatric ALL
Click Here to Manage Email Alerts
ORLANDO, Fla. — Variants in bone and fat differentiation genes within mesenchymal stem cells appeared associated with development of osteonecrosis among children with acute lymphoblastic leukemia aged younger than 10 years, according to findings from a multi-institutional study presented at the ASH Annual Meeting and Exposition.
The risk and incidence of therapy-induced osteonecrosis has limited the ability of clinicians to intensify treatment regimens for pediatric patients with ALL, especially those aged 10 to 20 years, according to study background. Because research has focused on that age group, little data on the genetic risk factors existed on patients aged younger than 10 years.
Seth E. Karol
Seth E. Karol, MD, a fellow in the department of pediatric hematology and oncology at St. Jude Children’s Research Hospital in Memphis, Tennessee, and colleagues hypothesized that genetic risk factors may be associated with a greater proportion of risk for osteonecrosis in the younger pediatric population.
“This study provides the first insight into factors which may predispose children under age 10 to develop osteonecrosis,” Karol told HemOnc Today. “Importantly, variants in glutamate receptor signaling genes were found to predispose to osteonecrosis in children under 10; this pathway was the most closely linked with the development of osteonecrosis in our prior study which was more representative of genetic influences in older children.
“We also show for the first time the importance of genetic variants influencing mesenchymal stem cells in the development of osteonecrosis,” Karol added. “By increasing our understanding of the pathophysiology involved in the development of osteonecrosis, this study may lead to better prevention or treatment of this side effect of leukemia therapy.”
Karol and colleagues evaluated genetic risk data from a discovery cohort of 82 patients of osteonecrosis and 287 controls with standard-risk ALL treated on a Children’s Oncology Group AALL0331 trial. Researchers then tested the genetic risk factors for replication in 810 children with high-risk ALL aged younger than 10 years.
In the discovery cohort, the most common variants identified included rs76599360 and rs77556622 which were in full linkage disequilibrium located near the BMP7 protein (OR = 22; 95% CI, 8.15-59.6).
The most replicated single nucleotide polymorphisms (SNPs) were located near BMP7 rs7561997 in the discovery (OR = 15; 95% CI, 5.64-39.7) and replication (OR = 8.44; 95% CI, 1-71.1) cohorts and near PROX1-AS1 rs1891059 in the discovery (OR = 6.48; 95% CI, 3.19-13.1) and replication (OR= 3.78; 95% CI, 1.42-10.1) cohorts.
The top replicated non-synonymous SNP was the variant rs34144324 in the glutamate receptor gene GRID2 in the discovery cohort (OR = 3.46; 95% CI, 2-5.98) and the replication cohort (OR = 10.8; 95% CI, 1.63-71.4).
Results of a meta-analysis of both cohorts indicated replicated BMP7 rs75161997 variant and PROX1-AS1 rs1891059 variant — as well as variant rs141059755 in NCRNA00251 — met the genome-wide threshold for significance of less than 5 x 10–8.
Additionally, replicated SNPs with a P < 1 x 10–5 demonstrated an enrichment in the enhancers that are active in mesenchymal stem cells. Further, a pathway analysis of the genes linked to the most frequent SNPs (P < .001) showed an enrichment in glutamate receptor signaling and adipogenesis pathways.
“The importance of [these] variants … in children less than 10 also confirms the findings of a recently completed genome-wide association study (Chang T, et al. Blood. 2014;124:367.) of osteonecrosis [in high-risk ALL patients], including patients of all ages and in which osteonecrosis occurred primarily in older children,” the researchers wrote. “These data provide new insights into osteonecrosis with implications for patients of all ages.” – by Anthony SanFilippo
References:
Karol SE, et al. Abstract 250. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Karol SE, et al. Blood. 2015;doi:10.1182/blood-2015-05-643601.
For more information:
Seth E. Karol, MD, can be reached at seth.karol@stjude.org.
Disclosure: One researcher reported consultant/advisory roles with Jazz Pharmaceuticals, Sigma Tau and Spectrum Pharmaceuticals and equity ownership of Merck.