|Orjuela, Manuela A.|
|Ramirez-ortiz, Marco A.|
|Suen, Ida H.|
Submitted to: CANCER
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/19/2012
Publication Date: 5/30/2012
Citation: Orjuela, M., Cabrera-Munoz, L., Paul, L., Ramirez-Ortiz, M., Liu, X., Mejia-Rodriguez, F., Medina-Sanson, A., Diaz-Carreno, S., Suen, I., Selhub, J. 2012. Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake. CANCER. DOI: 10.1002/cncr.27621. Interpretive Summary: Maternal intake of naturally occurring folate from vegetables during pregnancy is associated with lower risk of retinoblastoma (cancer of the eye) in offspring. We examined the association between retinoblastoma risk and maternal genetic variations in the genes for enzymes that carry out reactions involving folate, methylene tetrahydrofolate reductase and dihydrofolate reductase. 103 mothers of children with newly diagnosed retinoblastoma and 97 mothers who had healthy children from central Mexico were enrolled in the study. Maternal methylene tetrahydrofolate reductase variation was unrelated to the risk of having a child with retinoblastoma. The risk of having a child with retinoblastoma was associated with maternal genetic variation in dihydrofolate reductase and the risk was elevated significantly among those who reported taking folic acid supplements during pregnancy. Dihydrofolate reductase is necessary for converting synthetic folic acid into biological folate. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood cancer in a genetically susceptible subset of the population.
Technical Abstract: 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. 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 leads to 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. 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. 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.