Abstract
Based on observational studies, early age leukemia (EAL) was associated with maternal hormone exposure during pregnancy. We studied the association between genetic polymorphisms of estrogen metabolism and EAL. Using data from the Brazilian Collaborative Study Group of Infant Acute Leukemia (2000–2012), 350 cases and 404 age-matched controls and 134 mothers of cases and controls were genotyped to explore polymorphisms in genes of the estrogen metabolism pathway: CYP1B1 (c.1294C>G, rs1056836), CYP3A4 (c.-392A>G, rs2740574), CYP3A5 (c.219-237G>A, rs776746), GSTM1/GSTT1 deletions, and SULT1A1 (c.638G>A, rs9282861; and c.667A>G, rs1801030). Logistic regression was used to calculate the odds ratios (OR) with 95% confidence intervals (CIs), and unconditional logistic regression was used to estimate adjusted odds ratios (aORs) by ethnicity. Because of multiple testing, p values < 0.01 were significant after Bonferroni correction. SULT1A1 (c.638G>A) was associated to infant acute lymphoblastic leukemia and acute myeloid leukemia (AML) risk in males (additive model: aOR = 0.52; 95% CI: 0.29–0.95, p = 0.03; dominant model: aOR = 2.18; 95% CI: 1.17–4.05, p = 0.01, respectively). CYP1B1 polymorphism was associated with a decreased risk of AML either for non-white or female children (additive model: OR = 0.24; 95% CI: 0.08–0.76, p < 0.01; additive model: aOR = 0.27; 95% CI: 0.08–0.89, p = 0.03, respectively). Since polymorphisms of Cytochrome P450 genes presented gender-specific risk associations, we also investigated their expression. CYP1B1 was not expressed in 57.1% of EAL cases, and its expression varied by genotype, gender, and leukemia subtype. Maternal-fetal GSTT1 null genotype was associated with risk of EAL. This study shows that polymorphisms in genes of estrogen metabolism confer genetic susceptibility to EAL, mainly in males, and maternal susceptibility genes modify the risk for developing EAL in newborns.
Highlights
IntroductionThe acute leukemia causation pathway has been postulated to be a multistep process comprising an interaction between environmental (e.g., ionizing radiation or carcinogenic substances such as benzene, tobacco, and estrogen) and genetic susceptibility factors [1]
The acute leukemia causation pathway has been postulated to be a multistep process comprising an interaction between environmental and genetic susceptibility factors [1]
Based on the hypothesis that genetic polymorphisms of estrogen metabolism modulates the amount of carcinogenic compounds a precursor cell may be exposed, we evaluated five polymorphisms in CYP1B1, CYP3A5, GSTM1, GSTT1, and SULT1A1 in order to investigate whether these genetic changes modify the risk of developing Early age leukemia (EAL)
Summary
The acute leukemia causation pathway has been postulated to be a multistep process comprising an interaction between environmental (e.g., ionizing radiation or carcinogenic substances such as benzene, tobacco, and estrogen) and genetic susceptibility factors [1]. Together, these factors may cause genetic or epigenetic alterations, destabilizing normal physiological conditions. In order to test this hypothesis, we have previously demonstrated an association between maternal exposure to hormones (e.g., estrogen) before and during the first trimester of pregnancy and an increased risk of EAL. The rationale for the association between estrogen exposure and leukemogenesis in EAL was that estrogen metabolites lead to the formation of quinones and reactive oxygen species, promoting mutagenesis
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