Women with a common genetic mutation who took folic acid supplements during pregnancy were nearly four times as likely as other women to give birth to a child with retinoblastoma.
Researchers from Columbia University’s Mailman School of Public Health, Columbia University Medical Center, and several collaborating institutions, including the Hospital Infantil de Mexico, the Instituto Mexicano de Salud Publica, the Instituto Mexicano de Seguro Social, and the Vitamin Metabolism Laboratory at the Jean Mayer USDA Human Nutrition Research Center on AgingatTufts University, published the finding online in the journal Cancer.
In the Mexico-based study, researchers followed 103 mothers of children with a sporadic form of retinoblastoma, in which only one eye is affected, along with a control group of 97 mothers of healthy children. The women provided blood samples, which were tested for mutations on two genes involved with the body’s metabolism of folate—polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR). They were also interviewed regarding their use of folic acid supplements during pregnancy. Women with DHFR polymorphism who took folic acid supplements had a nearly threefold risk for having a child with retinoblastoma. There did not appear to be an increased risk in women with the polymorphism who did not take the supplements. The MTHFR polymorphism did not affect their risk.
Diagram of folic acid and DHFR metabolism
The findings suggest that, among women with the DHFR polymorphism, elevated retinoblastoma risk may occur only above a certain level of intake of synthetic folate (folic acid), but exactly what that level is remains to be determined. In addition to folic acid supplements, women in the study were likely to have consumed folic-acid-fortified wheat flour; however, the amount they consumed is unknown.
An estimated 17–19% of women have the DHFR polymorphism, according to research with the Framingham cohort and the Long Island Breast Cancer Study. The polymorphism in question involves a missing chunk of a non-coding section of the DHFR gene—specifically, a 19-base-pair deletion of intron 1A.
The CDC recommends that women take daily folic acid supplements beginning one month before getting pregnant. “Our study is very small and should certainly not be interpreted to suggest that women should stop taking folic acid supplements, which are crucial for preventing major birth defects of the baby’s brain and spine,” says first author Manuela A. Orjuela, MD, ScM, assistant professor of clinical environmental health sciences and pediatrics (oncology) at Columbia University Medical Center and a pediatric oncologist at NewYork-Presbyterian Morgan Stanley Children’s Hospital.
Along with supplements, women in the U.S. obtain folates through folic-acid-fortified foods, including flour, rice, and pasta, and through naturally occurring folates in egg yolk, orange juice, and some leafy vegetables. The naturally occurring folates are not metabolized by DHFR, notes Dr. Orjuela.
Previous research has linked folic acid supplements to increased risk for breast, prostate, and lung cancers; other research has shown that maternal supplements may reduce risk for childhood leukemia. The current study is the first to establish a connection with a pediatric cancer, showing that a maternal gene and maternal prenatal intake affect the child’s cancer risk. It is also the first to suggest gene-associated risk across generations.
In the U.S., retinoblastoma occurs in 1 in 15,000 births; one child is born with the disease every day. However, incidence varies substantially by country and may be higher in less industrialized countries. Retinoblastoma typically develops before the age of 5. Its most common sign, a visible whiteness in the pupil called a “cat's eye reflex,” or leukocoria, is particularly noticeable in photographs taken with a flash. The disease is fatal if untreated.
Funding for the study was provided by grants from the National Institutes of Health (R01 CA098180 and P30 ES009089). The authors make no disclosures.
June 5, 2012