RFC-180G>A Polymorphism in Case-Mother/Control-Mother Dyads Is Associated with Risk of Nephroblastoma and Neuroblastoma

Abstract

Aim: Embryonic tumors are associated with an interruption during normal organ development; they may be related to disturbances in the folate pathway involved in DNA synthesis, methylation, and repair. Prenatal supplementation with folic acid is associated with a decreased risk of neuroblastoma, brain tumors, retinoblastoma, and nephroblastoma. The aim of this study was to investigate the association between MTHFR rs1801133 (C677T) and RFC-1 rs1051266 (G80A) genotypes with the risk of developing nephroblastoma and neuroblastoma. Materials and Methods: Case-mother/control-mother dyad study. Samples from Brazilian children with nephroblastoma (n = 80), neuroblastoma (n = 66), healthy controls (n = 453), and their mothers (case n = 93; control n = 75) were analyzed. Genomic DNA was isolated from peripheral blood cells and/or buccal cells and genotyped to identify MTHFR C677T and RFC-1 G80A polymorphisms. Differences in genotype distribution between patients and controls were tested by multiple logistic regression analysis. Results: Risk for nephroblastoma and neuroblastoma was two-to fourfold increased among children with RFC-1 polymorphisms. An increased four-to eightfold risk for neuroblastoma and nephroblastoma was seen when the child and maternal genotypes were combined. Conclusion: Our results suggest that mother and child RFC-1 G80A genotypes play a role on the risk of neuroblastoma and nephroblastoma since this polymorphism may impair the intracellular levels of folate, through carrying fewer folate molecules to the cell interior, and thus, the intracellular concentration is not enough to maintain regular DNA synthesis and methylation pathways.

A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children’s Oncology Group

“…MTHFR 667C>T (rs1801133), one of the most highly studied variants with known functional effects on one-carbon metabolism, [37–39] had a null offspring association (RR: 0.99, 95% CI: 0.84–1.19) and a weak maternal association (RR: 1.16, 95% CI: 0.97–1.38). Two previous studies of candidate SNPs from folate-related genes identified SLC19A1 80G>A (rs1051266) as positively associated with neuroblastoma in Brazil [40, 41]. Montalvão-de-Azevedo et al found maternal carriers of the G had 3 times the risk of offspring with neuroblastoma and offspring carriers had approximately 2.5 times the risk, which was replicated by de Miranda et al [40, 41].…”

“…Two previous studies of candidate SNPs from folate-related genes identified SLC19A1 80G>A (rs1051266) as positively associated with neuroblastoma in Brazil [40, 41]. Montalvão-de-Azevedo et al found maternal carriers of the G had 3 times the risk of offspring with neuroblastoma and offspring carriers had approximately 2.5 times the risk, which was replicated by de Miranda et al [40, 41]. In NENA, we found no association (Maternal RR: 1.12, 95% CI: 0.96–1.32; offspring log-additive RR: 0.94, 95% CI: 0.79–1.11).…”

Base Excision Repair Gene Polymorphisms and Wilms Tumor Susceptibility

“…Folate pathway participates in DNA synthesis, methylation, and repair. Prenatal intake of folic acid is associated with a decrease in the risk of childhood malignancies including neuroblastoma and nephroblastoma [ 30 ]. A G80A (rs1051266) polymorphism in the RFC1 gene, encoding a folate transporter in the cell membrane, was found to associate with increased susceptibility to nephroblastoma and neuroblastoma in Brazilian children [ 30 ].…”

“…Polymorphisms in key BER genes may modify BER kinetics and capacity, which further alter cellular DNA repair ability and cause cell dysfunction, mutagenesis, and ultimately carcinogenesis [ 40 , 43 ]. Thus far, no evidence of linkage between BER SNPs and Wilms tumor has been reported; however, a few studies suggest the implication of DNA repair genes in Wilms tumor [ 28 , 30 ]. Due to their universal implications in carcinogenesis, we systematically investigated the association between SNPs within the BER pathway and Wilms tumor risk.…”

The association between RFC1 G80A polymorphism and cancer susceptibility: Evidence from 33 studies

“…Chango et al 36 indicated that individuals carrying AA genotype had higher plasma folate levels than those carrying GG genotype. Recently, increasing evidences have highlighted the importance of RFC1 G80A polymorphism in the pathogenesis of malignance 37 - 39 .…”