5,10‐methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of acute lymphoblastic leukemia (ALL) in Filipino children

Alcasabas, Patricia; Ravindranath, Yaddanapudi; Goyette, Gerard; Haller, Andrew; Rosario, Luz del; Lesaca-Medina, Maria Ysabel; Darga, Linda L.; Ostrea, Enrique M.; Taub, Jeffrey W.; Everson, Richard B.

doi:10.1002/pbc.21511

Cited by 46 publications

(40 citation statements)

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“…The MTHFR C677>T variant allele is present in 34% of Caucasians and 14% of African-Americans, whereas the A1298>C variant allele is present in 27-36% of Western Europeans with little allele frequency data in African-Americans [12,13]. The MTHFR gene variants are reported to be associated with increased risk of carcinogenesis [14][15][16].…”

Section: Introductionmentioning

confidence: 94%

Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Tantawy

El-Bostany

Adly

et al. 2010

Blood Coagulation & Fibrinolysis

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Genetic variations of the enzymes involved in chemotherapy metabolism in cancer patients may play a role in determining relapse and toxicity risks. Methotrexate is a key drug in acute lymphoblastic leukemia (ALL) treatment; it inhibits DNA replication by blocking the conversion of 5,10 methylene tetrahydrofolate to 5-methylene tetrahydrofolate by methylene tetrahydrofolate reductase (MTHFR). MTHFR is central to folate metabolism and has two common functional polymorphisms (C677>T and A1298>C). The present study aimed to assess the prevalence of MTHFR polymorphisms C677>T and A1298>C in Egyptian children with ALL and the relation to the frequency of drug-induced complications and relapse rate. Forty ALL patients were included in the study. They were treated according to modified ALL-BFM 90 protocol, and were followed up for 3.1-6.5 years. The severity and duration of hepatic, mucosal and infectious complications during therapy were reported. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay. The MTHFR C677>T polymorphic allele frequencies were 40, 27.5, and 32.5% for TT, CT, and CC genotypes, respectively among the studied ALL patients. The MTHFR A1298>C polymorphic allele frequencies were 40, 35, and 25% for AA, AC, and CC genotypes, respectively. Methotrexate therapy was significantly associated with increased grade III/IV toxicity in TT genotype: diarrhea in 81.3%, oral mucositis in 81.3%, elevated transaminases in 87.5%, neutropenia in 78.7% compared to values of 7.7, 7.7, 15.3, and 7.7% in CC genotype, respectively (P < 0.0001, P < 0.0001, P < 0.0001, and P U 0.03). The 677 TT genotype was significantly associated with relapse in 5 years in 56.3%, compared to 18.2% in CT and 0% in CC alleles. The overall 5 years survival was significantly lower in 677 TT (50%) compared with CC genotypes (92.3%) (P U 0.001). No significant relation was found between MTHFR A1298C polymorphism and the risks of therapy induced complications orrelapse rateinthestudied ALLpatients. MTHFR TTgenotype issignificantlyassociated withincreasedmucosalandhepatic toxicity during methotrexate therapy as well as increased relapse rate in childhood ALL. Because of the relatively high prevalence of the TT genotype in the studied Egyptian children with ALL, MTHFR gene polymorphisms should be studied in large multicenter studies; and dosage modification of methotrexate in the ALL treatment protocols should be considered based on the MTHFR gene pattern.

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Section: Introductionmentioning

confidence: 94%

Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Tantawy

El-Bostany

Adly

et al. 2010

Blood Coagulation & Fibrinolysis

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“…Five studies included samples from remission and those collected at diagnosis. [36][37][38][39]49,69 Only six studies 45,57,61,72,73,75 clearly stated that the samples were collected when the patients were in remission. The tissue origin for these studies varied from bone marrow, buccal swabs, Guthrie cards and peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

“…Pooling data from the 17 studies 29,33,[38][39][40][41][42][43][44][45][46][47][48][49][50][51] which have examined MTHFR C677T provided no evidence for a relationship between genotype and risk ( Table 2; Online Supplementary Figure S1; Online Supplementary Table S2). There was evidence of population stratification in the studies reported by Wiemels et al 38 and Balta et al, 40 as controls showed evidence of departure from HWE (P=0.02, 0.05).…”

Section: Meta-analysismentioning

confidence: 99%

“…MTHFR A1298C has been evaluated in 14 studies. 29,33,38,39,42,[44][45][46][47][48][49][50][51] Pooled analysis provided no evidence for a relationship between A1298C and ALL risk (Table 2; Online Supplementary Figure S1; Online Supplementary Table S2). Similarly pooling data from the four studies of the MTR A2756G polymorphism 42,44,47,52 provided no support for a relationship between A2756G genotype and risk (Table 2; Online Supplementary Figure S1; Online Supplementary Table S2).…”

Section: Meta-analysismentioning

confidence: 99%

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Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis

Vijayakrishnan¹,

Houlston²

2010

Haematologica

111

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To evaluate the contribution of candidate gene association studies to the understanding of genetic susceptibility to childhood acute lymphoblastic leukemia we conducted a systematic review and meta-analysis of published studies (January 1996-July 2009. Studies had to meet the following criteria: be case-control design, be studied by two or more studies, not be focused on HLA antigen genetic markers and be published in English. We identified 47 studies of polymorphic variation in 16 genes and acute lymphoblastic leukemia risk. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed. Of the 25 polymorphic variants studied, significant associations (P<0.05) were seen in pooled analyses for eight variants: GSTM1 (OR =1.16; 95%CI: 1.04-1.30), MTRR A66G (OR=0.73, 95%CI:0.59-0.91), SHMT1 C1420T (OR=0.79, 95%CI: 0.65-0.98), RFC1 G80A (OR=1.37, 95%CI: 1.11-1.69), CYP1A1*2A (OR=1.36, 95%CI:1.11-1.66), CYP2E1*5B (OR=1.99, 95%CI:1.32-3.00) NQO1 C609T (OR=1.24, 95%CI:1.02-1.50) and XRCC1 G28152A (OR=1.78, 95%CI:1.32-2.42). These findings should, however, be interpreted with caution as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While candidate gene analyses are complementary to genome-wide association studies, future analyses should be based on sample sizes commensurate with the detection of small effects and attention needs to be paid to study design.Key words: polymorphisms, acute lymphoblastic leukemia, risk, meta-analysis, false positive report probabilities. -analysis. Haematologica 2010;95(8):1405-1414. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Vijayakrishnan J and Houlston RS. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta IntroductionAcute leukemia is the major pediatric cancer in developed countries, affecting between 30-45 per 1,000,000 children each year.1 Dysregulated immune response to infection may be a cause of childhood acute lymphoblastic leukemia (ALL) 2 and epidemiological data are consistent with transplacental carcinogen exposure as a basis for infant leukemia associated with MLL gene fusion, 3 but the role of environmental carcinogenesis in ALL is currently undefined. It is, however, likely that the risk of ALL from environmental exposure is influenced by co-inheritance of multiple low-risk variants.The commonest method for identifying common low-risk variants is through association studies. These are based on comparing the frequency of polymorphic genotypes in cases and controls. Alleles positively associated with the disease are analogous to risk factors in epidemiology and may be causally related to disease risk or in linkage disequilibrium with disease-causing variants. There are a number of different methods of analyzing the risk associated with a specific variant. For simple bi-allelic polymorphisms, the odds ratio of disease can be derived by comparing allele frequencies in cases and controls. This ap...

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“…In general, the susceptibility due to genetic polymorphisms seems to be more evident for ALL than AML [9,[18][19][20], with few exceptions such as the Romanian population that seems to be particularly at risk for the development of AML in the presence of polymorphic variants of the MTHFR gene [21,22]. Some authors, however, found no correlation [23][24][25].…”

Section: Main Bodymentioning

confidence: 99%

Insights into maternal diet for the prevention of childhood leukaemia

Cantarella¹,

Ragusa²,

Tosi³

2018

Hematol Leuk

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Nutrition plays a crucial role in wellbeing and is being increasingly recognised as an environmental factor in the development of disease. During pregnancy, maternal diet influences foetal development, playing a role not only in the prevention of neural tube defects and malformations, but also in the susceptibility to disease later in life. Certain micronutrients, such as folates, are involved in the maintenance of genome integrity, which is compromised in cancer. A deficiency in these nutrients can therefore be relevant in carcinogenic processes. The early onset of childhood leukaemia implies that it originates already in utero, where environmental factors can interfere with the healthy development of the foetus. Population studies have found an association between maternal intake of folic acid and multivitamins and a reduced risk in the development of leukaemia in the offspring. Although the supplementation of vitamins is recommended during pregnancy, the adequate dosage and nutrient combinations need to be further elucidated to fully maximise their protective role.

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5,10‐methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of acute lymphoblastic leukemia (ALL) in Filipino children

Abstract: A1298C polymorphisms is associated with an increased risk for ALL in Filipino children. This may be due to a difference in leukemia biology or to a high prevalence of folate deficiency in Filipinos. Our study reiterates the gene and environment interaction in leukemogenesis.

Cited by 46 publications

References 24 publications

Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis

Insights into maternal diet for the prevention of childhood leukaemia

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