title: RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures.
abstract: BACKGROUND
  Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis, including RAS mutation (RASmut) in acute myeloid leukaemia (AML), which has been associated with intra-uterine chemical exposures. A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with early age leukaemia (EAL).
  
  
  METHODS
  Covariables of reference were MLL rearrangements (MLL-r), RASmut and NQO1 rs1800566 (C609T). Samples from 150 acute lymphoblastic leukaemia (ALL) and 85 AML were included. Maternal exposures were assessed using a structured questionnaire with demographic, personal habits and residence history information. Restriction fragment length polymorphism and denaturing high performance liquid chromatography were used to screen FLT3, KRAS, and NRAS mutations; direct sequencing was performed to validate the results. NQO1 polymorphism was detected by real-time allelic discrimination technique.
  
  
  RESULTS
  Overall, RASmut were detected in 28.7% of EAL cases; BRAFmut was found only in one AML patient. Higher rate of KRASmut was found in ALL (30.3%) compared to AML (20.8%) with MLL-r; RASmut showed an association with second-hand tobacco smoking exposures (OR, 3.06, 95% CI, 1.03-9.07). A considerable increased risk for EAL with the combination of RASmut and NQO1 609CT (OR, 4.24, 95% CI, 1.24-14.50) was observed.
  
  
  CONCLUSIONS
  Our data demonstrated the increased risk association between maternal smoking and EAL with MLL-r. Additionally, suggests that children second-hand tobacco exposures are associated with increased risk of EAL with RASmut modulated by NQO1 rs1800566 (C609T).
authors.forename: Francianne Gomes
authors.initials: FG
authors.lastname: Andrade
authors.forename: Juliana Montibeller
authors.initials: JM
authors.lastname: Furtado-Silva
authors.forename: Bruno Alves de Aguiar
authors.initials: BA
authors.lastname: Gonçalves
authors.forename: Luiz Claudio Santos
authors.initials: LC
authors.lastname: Thuler
authors.forename: Thayana Conceição
authors.initials: TC
authors.lastname: Barbosa
authors.forename: Mariana
authors.initials: M
authors.lastname: Emerenciano
authors.forename: André
authors.initials: A
authors.lastname: Siqueira
authors.affiliation: Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37, Rio de Janeiro/RJ 20231-050, Brasil. mpombo@inca.gov.br.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Pombo-de-Oliveira
mesh_terms: D000293:Adolescent; D000328:Adult; D001938:Brazil; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D005260:Female; D011905:Genes, ras; D006801:Humans; D007938:Leukemia / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D008297:Male; D018811:Maternal Exposure; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D016017:Odds Ratio; D011247:Pregnancy; D011379:Prognosis; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D014028:Tobacco Smoke Pollution; D051788:Myeloid-Lymphoid Leukemia Protein; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D020928:Mitogen-Activated Protein Kinases