FOLATE PATHWAY GENES ASSOCIATION AS A GENETIC RISK FACTOR FOR DEATHS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS FROM AN ADMIXED POPULATION IN THE BRAZILIAN AMAZON

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, a representing for approximately 30% of all pediatric cancers. Advances in the chemotherapy of childhood ALL, based on a cocktail of chemotherapy drugs, have resulted in survival rates of > 80%. Despite the clinical success of this treatment, around 20% of the children present serious toxicological complications and relapses, which confirms the fact that ALL is still one of the main causes of pediatric death. Polymorphisms in genes involved in folate biosynthesis have been proposed to increase the risk of relapses and toxicities in the treatment of childhood ALL. The objective of the study was to evaluate the role of seven polymorphisms in folate pathway genes as prognostic markers of death in children with ALL of a miscegenated population from the Brazilian Amazon region. The study included 138 patients diagnosed with ALL. The treatment of the patients was based on the protocol ALL IC-BFM 2002. The polymorphisms investigated included: rs2236225 (MTHFD1 G > A), rs1801133 (MTHFR G > A), rs1801394 (MTRR A > G), rs11545078 (GGH G > A), rs1800909 (GGH A > G), rs3758149 (GGH G > A) and rs1979277 (SHMT1 G > A). The samples were genotyped using a QuantStudio 12K Flex RealTime PCR System. The influence of the genetic variants on the risk of death was evaluated by the applying a multivariate logistic regression, which included age, sex and genetic ancestry to control for confounding effects. All statistical tests were considered significant at p < 0.05. The analyzes were run in the SPSS program v.25.0. 42 (30. 4%) of the investigated patients died during ALL treatment. Most deaths occurred during the consolidation or maintenance phases of treatment (88%). The causes of death involved disease progression due to relapse (n = 29. 69% of patients) and toxicities (n = 13. 31% of the patients, the most frequent were haematological, 61. 5% and infectious, 30.7 %). The analyzes showed a significant association of rs11545078 G > A polymorphism of the GGH gene with the risk of death. Homozygous AA patients had a three-fold increased risk of death during treatment (OR: 3.193; 95% CI: 0.840-12.135; P: 0.042). No significant associations in the polymorphisms investigated with the risk of death during the treatment of the disease were found. Our study demonstrates the role of homozygosity of rs11545078 G > A polymorphism of the GGH gene as a risk factor for death in children treated for ALL in the investigated sample.

 

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No conflict of interest has been declared by the author(s).

Publication History

Article published online:
23 October 2019