Abstract
The etiology of acute myeloid leukemia (AML) underlies the influence of genetic variants in candidate genes. The CYP2B6 enzyme detoxifies many genotoxic xenobiotics, protecting cells from oxidative damage. The CYP2B6 gene is subjected to a single-nucleotide polymorphism (G516T) with heterozygotes (GT) and homozygotes (TT) presenting decreased enzymatic activity. This case-control study aimed to investigate the association of CYP2B6 G516T polymorphism with the susceptibility of AML and its cytogenetic and clinical characteristics. Genotyping was performed on 619 AML patients and 430 healthy individuals using RCR-RFLP and a novel LightSNip assay. The major finding was a statistically higher frequency of the variant genotypes (GT and TT) in patients compared to the controls (GT:38.8% vs 29.8% and TT:9.3% vs 5.3% respectively) (p<0.001). More specifically, a significantly higher frequency of GT+TT genotypes in de novo AML patients (46.6%) and an immensely high frequency of TT in secondary AML (s-AML) (20.5%) were observed. The statistical analysis showed that the variant T allele was approximately 1.5-fold and 2.4-fold higher in de novo and s-AML respectively than controls. Concerning FAB subtypes, the T allele presented an almost 2-fold increased in AML-M2. Interestingly, a higher incidence of the TT genotype was observed in patients with abnormal karyotypes. In particular, positive correlations of the mutant allele were found in patients carrying specific chromosomal aberrations [-7/del(7q), -5/del(5q), +8, +21 or t(8;21)], complex or monosomal karyotypes. Finally, a strikingly higher frequency of TT genotype was also observed in patients stratified to the poor risk group. In conclusion, our results provide evidence for the involvement of the CYP2B6 polymorphism in AML susceptibility and suggest a possible role of the CYP2B6 genetic background on the development of specific chromosomal aberrations.
Highlights
Acute myeloid leukemia (AML) is defined as a clonal proliferation of immature hematopoietic progenitors with varying degree of myeloid differentiation in the bone marrow, peripheral blood, or extra medullary tissues [1]
In order to evaluate the potential impact of the G516T CYP2B6 polymorphism in AML susceptibility, we studied the distribution of the G516T CYP2B6 genotypes and allele frequencies in a large cohort of Greek patients (n = 619) with de novo or secondary AML and in healthy individuals (n = 430)
Stratification of de novo AML patients according to FAB classification showed that the most common FAB subtype was M4 in 23.6% of patients followed by M2 in 22.7%, M3 in 19.8%, M5 in 15.3%, M1 in 8.4%, M0 in 5.7%, M6 in 3.3% and M7 in 1.2%
Summary
Acute myeloid leukemia (AML) is defined as a clonal proliferation of immature hematopoietic progenitors with varying degree of myeloid differentiation in the bone marrow, peripheral blood, or extra medullary tissues [1]. AML represents the most frequent acute leukemia in adults with a peak of incidence at approximately 65 years, while is more rarely found in children [2]. It constitutes a broad range of disorders with marked clinical and biological heterogeneity. It can be divided in de novo AML and secondary AML (s-AML) which includes patients with an antecedent hematologic disease such as myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN), or patients with a preceding hematologic or non-hematologic neoplasm treated with chemotherapy and/or irradiation [3]. The etiology of the disease is currently unknown; the interaction between environmental exposure and genetic susceptibility has been postulated to be a possible cause for the development of AML [8]
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