Abstract
Acute Myeloid Leukemia (AML) is a group of genetically diverse hematopoietic malignancies arising from cell progenitors developing in the myeloid pathway or from primitive stem cells. Genetic susceptibility of AML may account for an increased risk of AML due to partial metabolism of or biocativation of carcinogens. Chemical compounds are metabolized by a two-tiered phase detoxifying system. Polymorphisms in these pathways may lead to DNA damage and development of AML. We determined the frequencies of carcinogen metabolism gene polymorphisms (CYP1A1, del{GSTM1} and del{GSTT1}) in a case control-study based on polymorphism analysis. Fifty-eight consecutively AML patients (median age 62 years) and 174 sex and age-matched control group were assessed by a PCR-RFLP assay. There were 51 de novo and 7 secondary AML. CYP1A1*2A and CYP1A1*2C polymorphisms were more frequent in CG than AML p 0.001 and in contrast, CYP1A1*3 and CYP1A1*4 were more frequent in AML than CG p 0.001. There were no differences in del{GSTM1} neither del{GSTT1} between AML and CG (p = 0.999 and p = 0.539). Odds ratio for AML in patients harboring CYP1A1*3 was 2.36 (95% CI 1.2 - 4.5), 2.38 for CYP1A1*4 (95% CI 0.8 - 6.8). Adjusted OR was 2.63 for CYP1A1*3 (95% CI 1.4 - 5.1) and 2.66 for CYP1A1*4 (95% CI 0.9 - 7.8). In the multivariate analysis CYP1A1*3 polymorphism was a risk factor for AML with an OR for 3.99 (95%CI 1.9 - 8.6). To the best of our knowledge this is the first study to show that CYP1A1*3 heterozygous genotypes increase the risk of AML. Our data support that inherited absence of this carcinogen detoxification pathway may be an important determinant of AML.
Highlights
Acute Myeloid Leukemia (AML) is a heterogeneous group of genetically diverse hematopoietic malignancies, arising from blood cell progenitors developing in the myeloid pathway or from primitive stem cells with multilineage potential
This translated into a 2.36-fold odds ratio risk for AML in carriers of heterozygous CYP1A1*3 and a 2.38-fold odds ratio risk for AML in carriers of mutated CYP1A1*4 (Table 2)
When analysing polymorphisms in phase-2 there were no differences found in del{GSTM1} frequencies between AML and control group (CG) (p = 0.999) neither del{GSTT1} frequencies (19% and 15.5%, AML respectively, and CG p = 0.539)
Summary
Acute Myeloid Leukemia (AML) is a heterogeneous group of genetically diverse hematopoietic malignancies, arising from blood cell progenitors developing in the myeloid pathway or from primitive stem cells with multilineage potential. AML is understood as a complex disease resulting from multiple genetics and epigenetics alterations within hematopoietic stem cell and/or progenitor cells that have their self-renewal, proliferation, differentiation and apoptotic pathways altered. Genetic aberrations found in AML are characterized by point mutations, gene rearrangements, deletions, amplifications
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