Impact of Cytochromes P450 3A4 and 2B6 gene polymorphisms on predisposition and prognosis of acute myeloid leukemia: an Egyptian case-control study

Abstract

Background It has been postulated that the interaction between environmental risk factors and genetic susceptibility is a possible cause for the development of acute myeloid leukemia (AML). Cytochrome P450 (CYP) detoxification enzymes are responsible for the elimination of oxidative stress. Genetic polymorphisms in these enzymes may cause AML due to enhanced accumulation of reactive oxygen species. To study the association between CYP3A4 (A290G) and CYP2B6 (G516T) gene polymorphisms and the predisposition and prognosis of AML, 50 upfront AML patients and 50 healthy individuals were genotyped for CYP2B6 (G516T) and CYP3A4 (A290G) single-nucleotide polymorphisms (SNPs) using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) technique. The polymorphisms were evaluated in relation to the response to chemotherapy and survival. Results CYP2B6 gene mutation carries a threefold risk of developing AML (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.3–6.9), whereas CYP3A4 gene mutation carries approximately fourfold risk (OR, 3.8; 95% CI, 1.4–10.1). The presence of combined gene mutation conferred about 15-fold increased risk of developing AML compared with the presence of a single gene mutation (OR, 14.8; 95% CI, 1.8–124.2). CYP3A4 gene mutation is associated with worse overall survival (P = 0.030). Conclusion CYP enzyme gene polymorphisms are associated with the development of AML. Elimination of oxidative stress in genetically susceptible individuals may decrease the risk of AML and may improve survival.

The role of polymorphic cytochrome P450 gene (CYP2B6) in B-chronic lymphocytic leukemia (B-CLL) incidence and outcome among Egyptian patients

“…STATA software version 17 was applied to calculate the sample size and the findings of Botros et al when they examined the influence of CYPs polymorphisms on Egyptian patients with AML, as this is the first study to test CYPs polymorphisms in CLL patients from Egypt [ 22 ]. Analysis for a matched case-control study revealed that the sample size would be 47 participants per group (ratio 1:1), using a power of (80%) and an alpha error of (5%), and the chance of exposure in the control group would be 28%.…”

Genetic Polymorphisms of Xenobiotics-Metabolizing Enzymes Contributing to Leukemia

“…Pakakasma et al, on the other hand, found no significant difference in the distribution of CYP3A4(A290G) polymorphism between case and control [42]. This disparity may be explained by differences in acute leukemia risk factors between children and adults [35].…”

“…AML is a group of diseases characterized by clonal expansion of immature myeloid blasts, resulting in hematopoietic failure [34]. Through the inactivation of enzymatic activity, certain SNPs at the CYP genetic loci (CYP2D6, CYP1A1, CYP3A5, and CYP2E1) may be considered risk factors for many types of cancer and hematological malignancies, such as AML, ALL, and myelodysplastic syndromes (MDS) [35].…”

“…A number of studies have been undertaken to determine the role of CYP450 polymorphisms in the development of AML leukemia; however, these yielded conflicting findings. Increased susceptibility to AML has been described by Botros et al, who state that A CYP2B6 gene mutation increases the risk of developing AML by threefold (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.3-6.9), whereas a CYP3A4 gene mutation increases the risk by approximately fourfold (OR, 3.8; 95% CI, 1.4-10.1) [35]. According to the dominant model, the T3801C polymorphism in CYP1A1 is associated with an increased risk of AML in Asians [14,36].…”

Screening of V617F mutation in JAK2 gene with acute myeloid leukemia in the Saudi population

“…AML is a highly heterogenous and CD34 + CD38 -myeloid progenitor hematopoietic malignant disorder (da Cunha Vasconcelos et al, 2021). The etiology of this disease is virtually unknown, but the relationship between environmental risk and genetic susceptibility is believed to be a potential trigger for the formation of AML (Botros et al, 2021). The rate of occurrence rises considerably with the age at about 35/1 000 000 people.…”