Abstract
Experimental and epidemiological data have shown that acute myeloid leukemia in early-age (i-AML) originates prenatally. The risk association between transplacental exposure to benzene metabolites and i-AML might be influenced by genetic susceptibility. In this study, we investigated the relationship between genetic polymorphisms in CYP2E1, EPHX1, MPO, NQO1, GSTM1 and GSTT1 genes, and i-AML risk. The study included 101 i-AMLs and 416 healthy controls. Genomic DNA from study subjects was purified from bone marrow or peripheral blood aspirates and genotyped for genetic polymorphisms by real-time PCR allelic discrimination, Sanger sequencing and multiplex PCR. Crude and adjusted odds ratios (OR, adjOR, respectively) with 95% confidence intervals (95% CI) were assessed using unconditional logistic regression to estimate the magnitude of risk associations. EPHX1 rs1051740 T>C was associated with i-AML risk under the co-dominant (adjOR 3.04, P = 0.003) and recessive (adjOR 2.99, P = 0.002) models. In stratified analysis, EPHX1 rs1051740 was associated with increased risk for i-AML with KMT2A rearrangement (adjOR 3.06, P = 0.045), i-AML with megakaryocytic differentiation (adjOR 5.10, P = 0.008), and i-AML with type I mutation (adjOR 2.02, P = 0.037). EPHX1 rs1051740-rs2234922 C-G haplotype was also associated with increased risk for i-AML (adjOR 2.55, P = 0.043), and for i-AML with KMT2A rearrangement (adjOR 3.23, P = 0.034). Since EPHX1 enzyme is essential in cellular defense against epoxides, the diminished enzymatic activity conferred by the variant allele C could explain the risk associations found for i-AML. In conclusion, EPHX1 rs1051740 plays an important role in i-AML’s genetic susceptibility by modulating the carcinogenic effects of epoxide exposures in the bone marrow.
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Acknowledgements
We kindly thank all children and their parents who participated in the study. We also thank Profª Ana Rossini for scientific advice, Elda Pereira Noronha and all technical staff of the Pediatric Hematology-Oncology Research Program of INCA for their work with childhood leukemia diagnosis, and all the collaborators of the Brazilian Study Group of Childhood Acute Myeloid Leukemia (IMol-AMLBSG). This work was supported by grants from the National Council of Technological and Scientific Development (CNPq #301594/2015-5) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ # E_26/110.169/2013).
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GDB wrote the manuscript. GDB, BAL and BAAG performed genotyping assays of cases and controls, and contributed to data collection and DNA samples preparation of controls. BAL contributed to experimental procedures set ups and statistical analyses. FGA, FVSB, ISC and GDB worked on the molecular characterization of cases. ETG worked on cases’ diagnosis. FHPB provided controls samples. MSPO contributed to the conception and critical analysis of the study and the manuscript.
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The study was performed in accordance with the 1964 Declaration of Helsinki and its later amendments. The Ethics and Scientific Committee of Instituto Nacional de Câncer and all collaborating Brazilian institutions have approved the study (CEP/CONEP #186.688; CEP/CONEP #626.268).
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Brisson, G.D., de Almeida Lopes, B., Andrade, F.G. et al. EPHX1 rs1051740 T>C (Tyr113His) is strongly associated with acute myeloid leukemia and KMT2A rearrangements in early age. Arch Toxicol 92, 2001–2012 (2018). https://doi.org/10.1007/s00204-018-2198-8
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DOI: https://doi.org/10.1007/s00204-018-2198-8