Mutations of ASXL1 are early events in acute myeloid leukemia (AML) leukemogenesis and have been associated with unfavorable prognosis. In this study, we investigated the type and frequency of ASXL1 mutations in a large cohort of patients with de novo or secondary AML (s-AML) and looked for correlations with cytogenetic findings and disease features. ASXL1 mutations were associated with older age, s-AML and higher peripheral leukocytosis. We observed more frequent co-occurrence of ASXL1 mutations with trisomy 8 and chromosome 11 aberrations but a negative correlation with myelodysplastic syndromes (MDS)-related cytogenetic abnormalities, especially -5/del(5q) and -7/del(7q). ASXL1 mutations were also found in other genetically defined AML subgroups such as those with t(9;22), inv(3)/t(3;3), t(8;21) or t(15;17); however, none of our inv(16) cases carried ASXL1 mutations. We detected two previously unreported ASXL1 mutations, p.IIe593Val and p.Cys688Tyr. Our findings suggest that ASXL1 mutations tend to cluster with specific clinical and cytogenetic profiles of AML patients.
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.
quinone oxidoreductase 1 (NQO1) enzyme detoxifies genotoxic products of oxidative stress. The corresponding gene is subject to an inactivating single-nucleotide polymorphism (C(609)T), which reduces detoxifying ability. The aim of this study was to investigate whether the C(609)T NQO1 inborn gene polymorphism is associated with an increased risk of BPD. Study Design Peripheral blood samples from 119 premature neonates ≤ 32 weeks of gestational age (42 BPD and 77 non-BPD) were used for DNA extraction. NQO1 genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. Results A significantly higher frequency of the NQO1 polymorphism was observed in BPD neonates compared with neonates without BPD. All neonates with ≤ 1,000 g birth weight who carried the mutant allele in heterozygous or homozygous state developed BPD. None of the BPD nonaffected group neonates with ≤ 1,000 g birth weight carried the NQO1 polymorphism. Conclusion The higher incidence of NQO1 mutants among BPD neonates as well as the presence of the mutant allele in all neonates with ≤ 1,000 g who developed BPD provided the first evidence for a possible pathogenetic role of the C(609)T polymorphism in BPD susceptibility due to the reduction or loss of NQO1 enzymatic activity.
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