A GRIN3A Polymorphism may be Associated with Glucocorticoid-Induced Symptomatic Osteonecrosis in Children with Acute Lymphoblastic Leukemia

Abstract

Aim: To evaluate the association between candidate genetic polymorphisms and glucocorticoid-induced osteonecrosis in Arab children treated for acute lymphoblastic leukemia. Methods: A total of 189 children treated for acute lymphoblastic leukemia were genotyped for four SNPs with allele discrimination assays. The incidence and timing of radiologically confirmed symptomatic grade 4 osteonecrosis were classified based on the Ponte di Legno toxicity working group consensus definition. Results: Thirteen children developed grade 4 osteonecrosis (6.8%), of whom 12 received the intermediate/high-risk treatment protocol. GRIN3A variant allele carriers had to stop dexamethasone therapy earlier resulting in significantly shorter duration of dexamethasone treatment (mean [95% CI]: 75.17 [64.28–86.06] vs 85.90 [81.22–90.58] weeks; p = 0.054) and lower cumulative dose (mean [95% CI]: 1118.11 [954.94–1281.29] vs 1341.14 [1264.17–1418.11] mg/m^2; p = 0.011). Conclusion: This is the first pharmacogenomics evaluation of the association between GRIN3A variants and glucocorticoid-induced osteonecrosis in Arab children.

Lay abstract

This study aimed at uncovering variants in the genetic material of Arab children, that might predispose them to develop a specific treatment-related adverse effect, during their therapy for acute lymphoblastic leukemia (a type of blood cancer). We looked at specific changes in the DNA of our patient cohort that might predispose them to develop treatment-induced osteonecrosis. Osteonecrosis is by definition a loss of blood flow to the bone tissue in one’s body, causing the bone to die. Osteonecrosis may be caused by long-term exposure to steroid-based medication, among which dexamethasone. Dexamethasone a main component of the combination of chemotherapeutic agents used to treat acute lymphoblastic leukemia. Our findings suggested that children who had one of the variants detected in a specific location of DNA, the GRIN3A gene, were more likely to develop osteonecrosis earlier and had to stop dexamethasone earlier during therapy.

Keywords::

• acute lymphoblastic leukemia
• Arab
• children
• dexamethasone
• genetic polymorphisms
• glucocorticoids
• GRIN3A
• osteonecrosis
• pharmacogenetics

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/pme-2020-0167

Author contributions

N Zgheib designed the research plan, completed the wet bench work with the help of her lab, analyzed datasets and wrote the manuscript. H El-Khoury, D Maamari designed the research plan, collected the data, contributed to the manuscript writing and provided meaningful discussion of main points. M Basbous designed the research plan and collected the data. R Saab designed the research plan, collected the data and revised the manuscript. S Muwakkit designed the research plan, collected the data and revised the manuscript. All authors have read and approved the final version of the manuscript.

Acknowledgments

The authors would like to thank the pediatric cancer tumor biorepository at AUBMC, and the Children’s Cancer Center of Lebanon.

Financial & competing interests disclosure

American University of Beirut Faculty of Medicine Naef K. Basile Cancer Institute tumor registry and data base, and American University of Beirut Faculty of Medicine Medical Practice Plan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The study was approved by the Institutional Review Board: BIO-2019-0122. Parents and subjects – as applicable – have agreed and signed during the informed consent process that peripheral blood is withdrawn for DNA analysis and that their clinical records are reviewed.

Data sharing statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.