AML is a form of cancer characterized by the infiltration of malignant cells to the blood, BM, and other tissues. Fifty years ago, AML was incurable; however, a few years ago, the prognosis improved and now AML is curable in 35%–40% of adult patients aged ≤60 years .
The exact causes of leukemia are still unknown despite widespread studies that investigated the mechanisms of the disease. It is believed that the exposure of DNA to reactive oxygen species in the hematopoietic stem cells is an important factor in the development of leukemia . CYP enzymes play an important role in the elimination of oxidative stress.
Genetic polymorphisms in these enzyme systems are associated with the reduction of CYP enzymes; thus, it can influence cancer susceptibility [8, 9].
The current work studied the possible association between CYP2B6 (G516T) and CYP3A4 (A290G) gene polymorphisms and susceptibility to AML in the Egyptian population and the association between CYP genotypes and the clinical presentation, hematological and cytogenetic findings, and treatment response in AML cases to justify whether such polymorphisms have any effect on the disease prognosis.
In this study, the mutant CYP2B6 genotypes were significantly higher in patients than controls (P = 0.017). Calculated risk estimation revealed that the mutant genotypes conferred a threefold increased risk of developing AML (OR, 3.3; 95% CI, 1.3–6.9).
In 2009, Bekroz et al. investigated the association between CYP2B6 gene polymorphism and the susceptibility to acute leukemia in the Turkish population. Their study included 80 acute leukemia patients (44 of the patients had acute lymphocytic leukemia [ALL] and 36 had AML) and 100 control subjects . Logistic regression analyses revealed a significant correlation between the CYP2B6 (G516T) polymorphism and patients with acute leukemia (OR, 2.481; 95% CI, 1.353–4.551; P = 0.003). In addition, in agreement with our results, Yuan et al. (2011) reported that the GT and GT + TT genotype frequencies of c.516G > T SNP were higher in ALL (37.5% and 42.7%, respectively; P < 0.01) and AML (37.2% and 40.9%, respectively; P < 0.01) than control subjects .
Regarding the CYP3A4 (A290G) SNP, the mutant genotypes were overrepresented in patients compared with the control subject (P = 0.006). The presence of the mutation, whether homozygous or heterozygous, carried an approximately fourfold increased risk of developing AML (OR, 3.8; 95% CI, 1.4–10.1).
In agreement with our data, Ali et al., in a case-control study involving 77 newly diagnosed AML cases and 72 age- and sex-matched healthy controls, reported a high frequency of the homozygous genotype (GG) in AML cases, although not statistically significant (P = 0.999). The G allele was significantly frequent in AML cases (P = 0.001; OR, 17.9; 95% CI, 4.041–78.903) .
Similar to our results, Voso et al., in a case-control study involving 160 cases of AML and 162 matched controls, reported a significantly higher prevalence of the polymorphic variant CYP3A4 (A290G) genes in AML cases than controls (9.4% vs 3.1%; P = 0.04), increasing the risk of developing AML to 3.2-fold (95% CI, 1.1–11.5) .
In contrast, Pakakasama et al. analyzed 107 children with ALL and 320 healthy controls for CYP3A4 (A290G) polymorphism and reported an insignificant difference in the distribution of the polymorphism between patients and controls . This difference may be explained by the variability of the risk factor for acute leukemia between children and adults.
Naoe et al. studied the CYP3A4 (A290G) polymorphism in 58 patients with t-AML/t-MDS and 150 Japanese healthy individuals and found that all subjects had the wild genotype, except 1 case that had a heterogeneous genotype, indicating a very low frequency or a lack of CYP3A4 (A290G) polymorphism in the Japanese population . This may be explained by ethnic variability.
The distribution of combined CYP2B6 and CYP3A4 gene mutations was also significantly increased in patients compared with controls (P = 0.003). The presence of combined gene mutation carried an approximately 15-fold increased risk of developing AML compared with the presence of a single gene mutation. To the best of our knowledge, no published study investigated the risk of this combined gene polymorphism and AML.
Similar to these results are those reported by Alazhary NM et al. (2015), who found no significant association between CYP2B6 polymorphism and CR, cytogenetic analysis, and OS . A cytogenetic analysis of 50 AML patients revealed abnormal cytogenetics in 32 patients (64%) and NCG in 18 patients (36%). Risk stratification according to the cytogenetic makeup of AML patients revealed 14 favorable (28%) and 36 nonfavorable patients (72%). In this study, no significant association was found between the presence of mutation in the CYP2B6 gene and cytogenetic risk stratification of AML patients. In contrast, a significant association was found between CYP3A4 gene mutation and unfavorable cytogenetic risk.
In another study, Sophia et al. (2014) reported a higher frequency of the mutant CYP2B6 (G516T) allele in patients with poor prognosis based on cytogenetic findings, indicating that the presence of the variant allele is probably related to specific chromosomal abnormalities conferring a poor prognosis .
Furthermore, we found that CYP3A4 (A290G) mutation was significantly associated with worse OS (P = 0.030). In contrast, OS was not affected by the presence of CYP2B6 gene mutations (P = 0.827). Patients carrying mutation of both genes had worse OS (P = 0.030) than patients with a single gene mutation.
DFS was not affected by the presence of CYP2B6 gene mutations (P = 0.352) or CYP3A4 gene mutation (P = 0.195). In addition, there was no significant difference in DFS between patients with a single gene mutation of one of the CYP2B6 and CYP3A4 genes compared with those with combined mutations (P = 0.265).
Similarly, Ali et al. (2013) reported that there was no significant association between CYP3A4 (A290G) SNP and different clinical or laboratory parameters and the early response to treatment, OS, and the DFS .