Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake

Abstract

Background Incidence of unilateral retinoblastoma varies globally suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is inversely associated with risk of retinoblastoma in offspring. Methods Using a case-control study design, we examined the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes, methylenetetrahydrofolate reductase (MTHFR677C>T, rs1801133) and dihydrofolate reductase (DHFR 19base pair deletion of intron 1a [DHFR19bpdel], rs70991108). In central Mexico, we enrolled 103 mothers of children with newly diagnosed unilateral retinoblastoma and 97 control mothers who had healthy children in an IRB approved study. Mothers were interviewed regarding perinatal characteristics including use of prenatal vitamin supplements and gave peripheral blood samples used for PCR-based genotyping of rs1801133 and rs70991108. Results The risk of having a child with unilateral retinoblastoma were associated with maternal homozygosity for DHFR19bpdel (OR=3.78, 95%CI:1.89,7.55; p=0.0002), even after controlling for child’s DHFR19bpdel genotype (OR=2.81, 95%CI:1.32,5.99; p=0.0073). 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 significantly elevated only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to risk of having a child with retinoblastoma. Conclusion Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biological folate is associated with 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.

Diagnostic Delay and Sociodemographic Predictors of Stage at Diagnosis and Mortality in Unilateral and Bilateral Retinoblastoma

“…Parents of children diagnosed with retinoblastoma between January 2000 and July 2010 and treated at the Hospital Infantil de México (HIM) in Mexico City were invited to participate in a study examining environmental contributors to sporadic (non-familial) Rb(18). …”

“…Parents were interviewed during initial consultation at the HIM ophthalmology service using a questionnaire designed specifically for this population(18, 22). Parents were queried about the date at which symptoms were first noted, as well as socio-demographic characteristics; such as the number of hours of transit time between home and hospital, parental education level (number of years of school completed), number of siblings currently living with the patient, combined total monthly income, and characteristics of the home in which the mother resided during her pregnancy with the patient.…”

Maternal diet during pregnancy and unilateral retinoblastoma

“…The Mexico City study assessed diet by interview with three open-ended questions about the foods mothers typically consumed for breakfast, lunch and dinner and consumption frequency of each food per week. Vegetable consumption may have been particularly important in this population because only 43% of case mothers and 53% of control mothers took multivitamins at any time during pregnancy, and this study took place before the adoption of folic acid fortification of flour in Mexico (19, 30). Fruit and vegetable consumption has been associated with lower risk of several cancers in adults (13).…”

Genotype Distribution of Dihydrofolatereductase Variants and their Role in Disease Susceptibility to Acute Lymphoblastic Leukemia in Indian Population: An Experimental and Computational Analysis

“…Functional polymorphisms in the DHFR gene can influence its expression or activity, thereby affecting the risk of folate-dependent diseases [19][20][21][22]. Polymorphisms in DHFR gene are also relevant in the context of sensitivity and resistance to antifolates [19,23,24] and antibacterial drugs, as they also affect the prognosis of such patients treated with these drugs.…”