A Pharmacogenetic Study of VDR fok1 and TYMS Polymorphisms and Their Association With Glucocorticoid-Induced Osteonecrosis in Egyptian Children With Acute Lymphoblastic Leukemia.

Dina Elharouni,Seham Gohar,Iman Sidhom,Nesreen Ali,Hassan Adwan,Dina Yassin,Iman Zaky

doi:10.3389/fonc.2018.00541

Dina Elharouni, Seham Gohar + Show 5 more

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https://doi.org/10.3389/fonc.2018.00541

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Abstract

Purpose: Osteonecrosis is a significant toxicity resulting from the treatment of pediatric Acute Lymphoblastic Leukemia (ALL). This study aimed to investigate the relationship between vitamin D receptor fok1 (VDR fok1) and thymidylate synthase (TYMS) gene polymorphisms with the glucocorticoid (GC) induced osteonecrosis (ON) in Egyptian pediatric ALL patients. In addition, to identify the possible association of genetic polymorphisms with other factors such as gender and ALL subtypes.Patients and Methods: A retrospective case-control study was conducted on 102 pediatric ALL patients under the age of 18 who were treated at Children Cancer Hospital Egypt according to St Jude SR/HR total XV protocol. The recruited patients were composed of 51 cases who developed GC-induced osteonecrosis and 51 age- and gender-matched patients who received glucocorticoids but remained osteonecrosis-free (controls). Genotyping of the VDR fok1 and TYMS genes was performed using restriction fragment length polymorphism (RFLP) and conventional PCR, respectively.Results: For the total 102 studied patients, the VDR fok1 single nucleotide polymorphisms (SNPs) frequency distribution were TT (8.8%), CT (34.3%), and CC (56.9%), while the TYMS tandem repeat gene variations were reported as 2R2R (20.6%), 2R3R (45.1%), and 3R3R (34.3%). VDR fok1 and TYMS polymorphic variants showed no association neither with gender; P-values 0.3808 and 0.1503, respectively, nor with ALL subtypes; P-values 0.9396 and 0.6596, respectively. The VDR fok1 polymorphisms showed a significant association with the development of ON; P-value = 0.003, on the other hand, TYMS tandem repeats did not show significant impact on osteonecrosis development; P-value = 0.411.Conclusion: This study showed a significant association between the VDR fok1 polymorphism and osteonecrosis. Such clinical pharmacogenetics results would be promising to discuss the possibility of dose adjustments aiming a regimen with the highest efficacy and least toxicity.

Highlights

Acute Lymphoblastic Leukemia (ALL) is the most prevalent cancer type in children [1]
For the total of 102 patients included in this study population, the Vitamin D Receptor (VDR) fok1 Single Nucleotide Polymorphisms (SNPs) frequency distribution were The homozygous mutant type (TT) (8.8%), CT (34.3%), and CC (56.9%)
The VDR fok1 and Thymidylate Synthase (TYMS) polymorphic variants showed no association with P-values of 0.3808 and 0.1503 respectively

Summary

Introduction

Acute Lymphoblastic Leukemia (ALL) is the most prevalent cancer type in children [1]. Significant toxicities remain a major risk factor that causes long-term morbidity and decreased quality of life [3]. Glucocorticoid (GC)-induced-Osteonecrosis (ON) is a challenging complication encountered during modern chemotherapy for childhood ALL. Osteonecrosis known as Avascular Necrosis (AVN) has been increasingly reported in pediatric ALL and presents a challenging complication [3]. It is a disabling clinical disease characterized by a decrease in osteoblastic activity and increased bone resorption [2]. GC-induced-ON is considered a multifactorial disease resulting from clinical risk factors as age, gender, and race as well as genetic factors [4]. Several research investigations have demonstrated that genetic polymorphisms in drug-targeted genes are highly associated with inter-individual differences in the efficacy and toxicity of the regimen

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