Incidence of unilateral retinoblastoma (Rtb) varies geographically(1). In the US, incidence is highest among Latino children(2). Little is known regarding its etiology. Median age for diagnosis of unilateral Rtb is 23 months, suggesting that tumor genesis begins during fetal development or infancy. In our case-control study in central Mexico, we hypothesized that maternal intake of folate and variations in genes regulating folate metabolism might predict incidence. Initial results show that maternal homozygosity for a 19 base pair (bp) deletion in intron-1a of the dihydrofolate reductase (DHFR) gene (DHFR19bpdel/del) predicts having a child with unilateral Rtb, and risk appears greater in mothers who took folic acid supplements in their 1st trimester of pregnancy. DHFR is critical for reducing folic acid and converting it into tetrahydrofolate. Physiologic folate is naturally occurrng in some vegetables and other foods, while folic acid is the synthetic form found in fortified foods and vitamin supplements. In the Framingham cohort, composed of older adults, participants with DHFR19bpdel/del are at an increased risk of having elevated levels of circulating unmetabolized folic acid (cUMFA), particularly when daily folic acid intake exceeds 500 micrograms(3,4). This threshold is well below the tolerated upper limit (UL) and is less than the Dietary Reference Intake (DRI) for pregnant women(5). Women with DHFR19bp del/del have an increased risk for breast cancer, but only among those taking vitamin supplements(6). Mothers in our study were interviewed using a validated Food Frequency Questionnaire (FFQ) to capture current and prenatal diet and supplement intake(7,8). Mexico began mandatory wheat flour fortification with folic acid in late 2000(9);however, existing nutrient content tables in Mexico do not account for folic acid from fortified wheat flour. Data on total folic acid intake is therefore not available fr our study mothers. We hypothesize that the increased risk we found associated with maternal DHFR19bpdel/del is mediated through maternal levels of cUMFA. We propose that mothers of Rtb cases are more likely to have elevated cUMFA than mothers of controls. In addition, we hypothesize that mothers with DHFR19bpdel/del will have higher levels of cUMFA when their intake of folic acid from fortified foods and supplements is moderately elevated. We propose 1) to measure cUMFA in stored samples from mothers of 167 children with unilateral Rtb and 150 controls in order to examine whether risk of retinoblastoma associated with DHFR19bpdel/del is associated with cUMFA;and 2) to update our Mexican nutrient composition tables to account for folic acid fortification, in order to calculate maternal intake of synthetic folic acid in our stud mothers using data already captured from the FFQ. We will examine whether levels of cUMFA in our mothers are predicted by total intake of folic acid, and whether this association varies wit DHFR genotype. Our proposed study is the first to examine risk of a pediatric tumor associated with accumulation of cUMFA and impaired maternal reduction of ingested folic acid. Results of our study could significantly affect both public policy, and our understanding of pediatric carcinogenesis.

Public Health Relevance

To examine whether risk of retinoblastoma (Rtb) is associated with maternal inability to metabolize folic acid (FA) we propose to measure unmetabolized FA in stored samples from mothers of Mexican children with Rtb and their healthy controls. We will update our nutrient database to account for FA fortification of flour and will calculate maternal intake of synthetic FA to examine if intake predicts levels of unmetabolized FA and disease risk. This study is the first to examine risk of a pediatric tumor associated with impaired maternal reduction of ingested FA and could affect both public policy, and our understanding of pediatric carcinogenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Epidemiology of Cancer Study Section (EPIC)
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Su, Joseph
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Columbia University (N.Y.)
Public Health & Prev Medicine
Schools of Public Health
New York
United States
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Kamihara, Junne; Ma, Clement; Fuentes Alabi, Soad Linneth et al. (2017) Socioeconomic status and global variations in the incidence of neuroblastoma: call for support of population-based cancer registries in low-middle-income countries. Pediatr Blood Cancer 64:321-323
Castro-Magdonel, Blanca Elena; Orjuela, Manuela; Camacho, Javier et al. (2017) miRNome landscape analysis reveals a 30 miRNA core in retinoblastoma. BMC Cancer 17:458
García-Chequer, A J; Méndez-Tenorio, A; Olguín-Ruiz, G et al. (2016) Overview of recurrent chromosomal losses in retinoblastoma detected by low coverage next generation sequencing. Cancer Genet 209:57-69
García-Chequer, A J; Méndez-Tenorio, A; Olguín-López, G et al. (2016) Illumina next generation sequencing data and expression microarrays data from retinoblastoma and medulloblastoma tissues. Data Brief 6:908-16
Ramírez-Ortiz, Marco A; Ponce-Castañeda, M Veronica; Cabrera-Muñoz, M Lourdes et al. (2014) Diagnostic delay and sociodemographic predictors of stage at diagnosis and mortality in unilateral and bilateral retinoblastoma. Cancer Epidemiol Biomarkers Prev 23:784-92
Mejía-Rodríguez, Fabiola; Neufeld, Lynnette M; García-Guerra, Armando et al. (2014) Validation of a food frequency questionnaire for retrospective estimation of diet during the first 2 years of life. Matern Child Health J 18:268-285