A Molecular Epidemiology Study On The Associations Between The Mthfr Polymorphisms And Genetic Susceptibility Of Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The incidence of childhood ALL was 4.75 per one hundred thousand people. Approximately 12,000 new ALL cases were diagnosed each year in China.To date, the mechanisms on the occurrence of ALL remain largely unknown. Epidemiologic, molecular biological and genetic studies have identified that many environmental and genetic factors may contribute to the etiology of childhood ALL. Epidemiologic studies have demonstrated that high consumption of personal character (e.g., virus, hematopathy) and environmental exposure (e.g., housing painting, maternal infection during pregnancy, and long-term exposure to radiation) may increase the risk of ALL. However, the vegetables and fruits in dietary may decrease the risk of ALL. Folic acid is essential for both the synthesis of nucleotide precursors of DNA and cellular methylation reactions, and therefore, low folate intake may be associated with the increased risk for a number of childhood ALL. Methylenetetrahydrofolate reductase (MTHFR) is one of the crucial enzymes in folate metabolism and single nucleotide polymorphisms (SNPs) in the MTHFR gene may alter the activity of some enzymes, which was involved in the folate metabolism pathway. We hypothesized that the MTHFR polymorphisms are associated with the susceptibility of childhood ALL.To test the hypothesis, we conducted a case-control study to evaluate the association of environmental factors, MTHFR polymorphisms with childhood ALL in Chinese population by cross-sectional, serological epidemiologic and molecular epidemiologic studies.Part 1Investigation of the Risk Factors of Childhood Acute Lymphoblastic LeukemiaObjective: Epidemiologic studies have identified that many environmental and genetic factors may contribute to the etiology of childhood ALL. However, the results of the relationship remain conflicting.Methods: A population-based case-control study was conducted, including 291 pathologically-confirmed childhood ALL and 466 cancer-free controls in Jiangsu province to explore the environmental and genetic risk factors.Results: The percents of polyembryony, premature delivery and radiation exposure in the case group were significantly higher than that in the control group. The percents of artificial feeding, congenital diseases, immunologic derangemental diseases and infectious diseases in the case group were higher than the control groups (P < 0.001). The pronounced increased risk was found in the maternal radiation exposure (P < 0.001). Moreover, the paternal drinking and housing painting increased the off-spring risk of ALL. The percent of the patients living near the chemical plant was significantly higher than the control group (16.5% vs. 8.4%,P = 0.001).Conclusions: Polyembryony, premature delivery, radiation exposure, maternal radiation, paternal drinking, housing painting and living near the chemical plant increased the off-spring risk of ALL. However,artificial feeding, with history of congenital diseases, immunologic derangemental diseases and infectious diseases decreased the risk of childhood ALL. Suspicious risk factors of leukemia should be avoided in order to reduce the incidence of childhood leukemia.Part 2MTHFR Polymorphisms Are Associated with Risk of Childhood Acute Lymphoblastic LeukemiaObjective: MTHFR, involved in DNA methylation and nucleotide synthesis, is thought to be associated with a decreased risk of adult and children acute lymphoblastic leukemia (ALL). Accumulating evidence has demonstrated that two common genetic variants, C677T and A1298C, were associated with cancer risk. We hypothesized that these two variants are associated with childhood ALL susceptibility and influence serum MTHFR level.Methods: In a hospital-based matched case-control study, a total of 361 childhood ALL cases and 508 cancer-free controls were genotyped for these polymorphisms and ELISA were used to detecte the serum MTHFR level.Results: Compared with the 677CC genotypes, the 677TT genotype was associated with a statistically significantly decreased risk of childhood ALL [Odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.32-0.88]. Besides, a pronounced reduced risk of ALL was observed among low risk and medium risk ALL and B-phenotype ALL. Moreover, the mean serum MTHFR level was 8.01 ng/mL (±4.38) in the cases and 9.27±4.80 ng/mL in the controls (P < 0.001), and MTHFR level in subjects with 677TT genotype was significantly higher than those with 677CC genotype (P = 0.010) and 677CT genotype (P = 0.043) in controls.Conclusions: MTHFR polymorphisms may contribute to the reduced childhood ALL risk in Chinese population.Part 3MTHFR Polymorphisms Contribute to Genetic Susceptibility to Acute Lymphoblastic Leukemia Risk: A Meta-analysisObjective: Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA methylation and nucleotide synthesis. Accumulated evidence has demonstrated that C677T and A1298C polymorphisms of MTHFR gene are associated with risk of acute lymphoblastic leukemia (ALL), but the results were inconclusive. To derive a more precise estimation of association between the MTHFR polymorphisms and risk of cancer, we performed a meta-analysis on all eligible case–control studies to estimate the overall cancer risk of these two polymorphisms and to quantify the potential between-study heterogeneity.Methods: A meta-analysis of 28 studies with 4,240 cases and 9,289 controls was performed.Results: MTHFR 677TT genotype showed a reduced risk of ALL compared with 677CC genotype (OR = 0.76, 95% CI = 0.61-0.94), especially among Caucasian population (OR = 0.68, 95% CI = 0.51-0.90). Moreover, significantly increased ALL risk was found among childhood in the comparison of 1298CC versus AA genotype (OR = 1.21, 95% CI = 1.02-1.43 for 1298CA vs. AA; OR = 1.21, 95% CI = 1.01-1.45 for 1298CA/CC vs. AA).Conclusions: MTHFR C677T and A1298C polymorphisms may contribute to the risk of ALL.Part 4MTHFR Polymorphisms Are Associated with Methotrexate Elimination after High-Dose InfusionObjective: Methotrexate is an antifolate chemotherapeutic agent that has been widely used in the treatment of ALL. Study of high-dose methotrexate (HD-MTX) in the treatment of children with acute lymphoblastic leukemia (ALL) in the time of the blood concentration of children with physiological and pathological status of the relationship, to provide basis for clinical treatment, find effects of the drug in the body to eliminate factors, and provides clues of Methotrexate for the child population pharmacokinetics study.Methods: One hundred and six cases of childhood ALL undergoing HD-MTX chemotherapy were included in the study to analysis the factors on the impact of the elimination of MTX.Results: The serum MTX level was 0.73±0.80μmol/L at 44 h after high-does methotrexate treatment, 0.21±0.28μmol/L at 68 h, and the overall number with delayed methotrexate elimination was 48 (44.0%). There was no statistically different between the different MTHFR C677T polymorphisms and serum MTX levels (P = 0.533 for 44 h and P = 0.566 for 68 h). The same result was observed among the MTHFR A1298C polymorphisms.Conclusions: MTHFR C677T and A1298C polymorphisms were not statistically associated with a vulnerability to methotrexate level or elimination.