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Open Access Research article

RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures

Francianne Gomes Andrade1, Juliana Montibeller Furtado-Silva12, Bruno Alves de Aguiar Gonçalves1, Luiz Claudio Santos Thuler3, Thayana Conceição Barbosa1, Mariana Emerenciano1, André Siqueira4, Maria S Pombo-de-Oliveira1* and Brazilian Collaborative Study Group of Infant Acute Leukaemia

Author Affiliations

1 Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37, Rio de Janeiro/RJ 20231-050, Brasil

2 Great Ormond Street Hospital, London, United Kingdom

3 Clinical Research Program, Research Centre, Instituto Nacional de Câncer, INCA, Rio de Janeiro, Brazil

4 Universidade do Estado do Amazonas, Manaus, AM, Brazil

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BMC Cancer 2014, 14:133  doi:10.1186/1471-2407-14-133

Published: 26 February 2014

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).

Keywords:
RAS mutation; NQO1; MLL; Tobacco smoking exposures; Childhood leukaemia