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Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase ( DHFR ) and prenatal folic acid intake
Author(s) -
Orjuela Manuela A.,
CabreraMuñoz Lourdes,
Paul Ligi,
RamirezOrtiz Marco A.,
Liu Xinhua,
Chen Jia,
MejiaRodriguez Fabiola,
MedinaSanson Aurora,
DiazCarreño Silvia,
Suen Ida H.,
Selhub Jacob,
PonceCastañeda M. Veronica
Publication year - 2012
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.27621
Subject(s) - medicine , methylenetetrahydrofolate reductase , odds ratio , pregnancy , confidence interval , genotype , obstetrics , physiology , gastroenterology , genetics , biology , gene
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 [ MTHFR 677C→T]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase ( DHFR ) (a 19‐base‐pair deletion of intron 1a [ DHFR 19bpdel]; 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 DHFR 19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89‐7.55; P = .0002), even after controlling for the child's DHFR 19bpdel 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), DHFR 19bpdel‐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. Cancer 2012. © 2012 American Cancer Society.