Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children

Abstract

Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11–5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62–78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42–191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94–31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05–6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19–31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.

Genotype Analysis of ABCC1, NCF4 and CBR3 Polymorphism and the Association With Childhood Acute Lymphoblastic Leukemia in Mexican Childhood Population

“…Kunická T. and Souček P., ( Kunická and Souček 2014 ) mentioned that resistance to multiple drugs has one of the most important causes of cancer treatment failure, ABC transporters are membrane-bound proteins that participate in cell defense mechanisms, hence their function is to prevent toxicity as carcinogenesis on the one hand, but may contribute to resistance of tumor cells to a number of drugs, including chemotherapeutics. Zaruma-Torres F et al ( Zaruma-Torres et al, 2016 ) in 2016 found that the ABCB1 rs1045642 and ABCC5 rs3792585 polymorphisms were associated with an increased risk of ALL in Mexican children. In the current study, we determinate the impact of three gene polymorphisms involved in the metabolism of antineoplastic drugs, such as the NCF4 rs1883112, CBR 3 rs1056892 and ABCC1 rs3743527 polymorphisms, we also provided frequencies of this variants and identify any association with the development of ALL in children.…”

“…Kunická T. and Souček P., (Kunická and Souček 2014) mentioned that resistance to multiple drugs has one of the most important causes of cancer treatment failure, ABC transporters are membrane-bound proteins that participate in cell defense mechanisms, hence their function is to prevent toxicity as carcinogenesis on the one hand, but may contribute to resistance of tumor cells to a number of drugs, including chemotherapeutics. Zaruma-Torres F et al (Zaruma-Torres et al, 2016) in 2016 found that the ABCB1 rs1045642 and ABCC5 rs3792585 polymorphisms were associated with an increased risk of ALL in Mexican children.…”

“…It is evident that, although there are many factors that are involved in the development of leukemia, genetic factors play a very important role since within the genes that are involved in different cellular metabolic pathways, some of them seem to have more importance. Apparently, the folate route constitutes a very important pathway, such is the case of the work reported by Zaruma-Torres F et al in 2016(Zaruma-Torres et al, 2016 who determined the associations between six SNPs in four genes related to the folate transporter pathway, to determine a significant relationship with the appearance of ALL in Mexican children, concluding that certain genetic polymorphisms related to the folate transport route, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642 and ABCC5 rs3792585, were associated with an increased risk of ALL in Mexican children. These results coincide, although to a lesser extent with what was found in our work, in which other polymorphisms are related to an increased susceptibility to ALL, such as the case of NCF4 rs1883112, became evident since this factor NCF4 could influence the susceptibility of presenting ALL through this polymorphism, as it hinder the action of folic acid and promote the risk of developing ALL, possibly by making it difficult to transform the folic acid to THF, through the de-hydro folate reductase dDHFR which is dependent on NADPH oxidase.…”

State of Art of Cancer Pharmacogenomics in Latin American Populations

“…Mutations in the CYP1A1 and GSTM1 genes were relevant in oral cancer in Latin Americans [149], also detected in Asians [150,151,152]. The hRAD54 , hMSH2 , ABCB1 , ABCC5 , COL18A1 , and SLC19A1 genes were consistent with lymphoma and leukemia in Latin Americans [153,154,155,156], as well as some Caucasians and Asians [157,158,159,160]. The RB1 gene was related with retinoblastoma in Latin Americans [161,162], and the TNFα and TP53 genes with cervical cancer [163,164,165,166,167,168].…”

A Bibliometric Analysis of Mexican Bioinformatics: A Portrait of Actors, Structure, and Dynamics

“…The lower left quadrant of Figure 5 has themes of low centrality and density that can represent emerging or disappearing themes. Within the theme “leukemia” we found the high occurrence concepts like “lymphoblastic”, which implies that it could be an emergent theme of specialization in the study of leukemia currently known as one of the biggest health problems in Mexican children [ 44 , 45 ]. Another theme that stands out is “networks”, where high occurrence concepts, such as “regulatory”, “coli” suggests that this theme has been influenced by one of the pioneering topics (gene regulation) of Mexican bioinformatics led by Dr. Collado-Vides and additional terms like “system”, “model” suggest an integrative stage of the theme for the study of gene regulation.…”