Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake.
BACKGROUND
The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring.


METHODS
The authors used a case-control study design to examine the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes methylenetetrahydrofolate reductase (MTHFR) (a cytosine-to-thymine substitution at nucleotide 677 [MTHFR677C→T]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase (DHFR) (a 19-base-pair deletion of intron 1a [DHFR19bpdel]; rs70991108). In central Mexico, 103 mothers of children with newly diagnosed unilateral retinoblastoma were enrolled in an institutional review board-approved study along with a control group of 97 mothers who had healthy children. Mothers were interviewed regarding perinatal characteristics, including use of prenatal vitamin supplements, and gave peripheral blood samples, which were used for polymerase chain reaction-based genotyping of rs1801133 and rs70991108.


RESULTS
The risk of having a child with unilateral retinoblastoma was associated with maternal homozygosity for DHFR19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89-7.55; P = .0002), even after controlling for the child's DHFR19bpdel genotype (odds ratio, 2.81; 95% confidence interval, 1.32-5.99; P = .0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel-associated risk was elevated significantly only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to the risk of having a child with retinoblastoma.


CONCLUSIONS
Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biologic folate was associated with an increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population.
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA. mao5@columbia.edu
Manuela A
MA
Orjuela
Lourdes
L
Cabrera-Muñoz
Ligi
L
Paul
Marco A
MA
Ramirez-Ortiz
Xinhua
X
Liu
Jia
J
Chen
Fabiola
F
Mejia-Rodriguez
Aurora
A
Medina-Sanson
Silvia
S
Diaz-Carreño
Ida H
IH
Suen
Jacob
J
Selhub
M Veronica
MV
Ponce-Castañeda
D016022:Case-Control Studies; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D019572:Retinal Neoplasms / Q000209:etiology / Q000235:genetics*; D012175:Retinoblastoma / Q000209:etiology / Q000235:genetics*; D012306:Risk; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase