title: Polymorphisms in CYP1B1, CYP3A5, GSTT1, and SULT1A1 Are Associated with Early Age Acute Leukemia.
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.
authors.affiliation: Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
authors.forename: Bruno Almeida
authors.initials: BA
authors.lastname: Lopes
authors.affiliation: Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Emerenciano
authors.affiliation: Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
authors.forename: Bruno Alves Aguiar
authors.initials: BA
authors.lastname: Gonçalves
authors.affiliation: Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
authors.forename: Tállita Meciany
authors.initials: TM
authors.lastname: Vieira
authors.affiliation: Department of Biochemistry, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Ana
authors.initials: A
authors.lastname: Rossini
authors.affiliation: Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Pombo-de-Oliveira
mesh_terms: D017668:Age of Onset; D015239:Arylsulfotransferase / Q000235:genetics*; D001938:Brazil / Q000208:ethnology; D016022:Case-Control Studies; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000208:ethnology / Q000235:genetics*; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000208:ethnology / Q000235:genetics*; D012737:Sex Factors
chemical_list: C585496:CYP1B1 protein, human; C510164:CYP3A5 protein, human; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human