Increased Risk of Acute Myeloid Leukemia in Patients with <i>CYP</i>1<i>A</i>1 Polymorphisms

Abstract

Acute Myeloid Leukemia (AML) is a group of genetically diverse hematopoietic malignancies arising from cell pro genitors 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 ( CYP 1 A 1, del { GSTM 1} and del { GSTT 1}) 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. CYP 1 A 1 * 2A and CYP 1 A 1 * 2C polymorphisms were more frequent in CG than AML p < 0.001 and in contrast, CYP 1 A 1 * 3 and CYP 1 A 1 * 4 were more frequent in AML than CG p < 0.001. There were no differences in del { GSTM 1} neither del { GSTT 1} between AML and CG (p = 0.999 and p = 0.539). Odds ratio for AML in patients harboring CYP 1 A 1 * 3 was 2.36 (95% CI 1.2 - 4.5), 2.38 for CYP 1 A 1 * 4 (95% CI 0.8 - 6.8). Adjusted OR was 2.63 for CYP 1 A 1 * 3 (95% CI 1.4 - 5.1) and 2.66 for CYP 1 A 1 * 4 (95% CI 0.9 - 7.8). In the multivariate analysis CYP 1 A 1 * 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 knowl edge this is the first study to show that CYP 1 A 1 * 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.