Folate Deficiency, Metabolism & Sporadic Retinoblastoma

Summary

Principal Investigator: Manuela Orjuela
Abstract: The objective of this study is to examine whether mutations in maternal and infant genes regulating folate metabolism are associated with an increased risk for the development of sporadic retinoblastoma. Environmental factors associated with poor living conditions may increase the risk of tumor formation, as the incidence of unilateral retinoblastoma is higher in several less affluent regions of the world. Mutations in the retinoblastoma gene, RB1 in germinal or dividing retinal cells result in tumor development. Most mutations occur at methylated cytosines, suggesting that abnormalities in methyl transfer may lead to mutagenesis. Folate, a regulator of methyl group transfer, is normally found in high concentrations in neural tissues and its deficiency can lead to mutagenesis through impaired methyl group transfer and pyrimidine synthesis. Risk for having a child with retinoblastoma is increased in women who do not take prenatal vitamin supplements and consume fewer folate-containing foods during pregnancy. The C677T and A1298C mutations in the methylene tetrahydrofolate reductase (MTHFR) gene and the A66G mutation in the methionine synthetase (MTRR) gene are common mutations in folate metabolizing enzymes genes which result in less functional enzymes. These act synergistically with low folate and co-balamin (B12) intake and increase the risk for neural tube defects. We hypothesize that decreased folate availability, because of poor intake, combined with less functional MTHFR and MTRR enzymes during key periods of retinal formation, in utero and in early infancy will lead to development of sporadic retinoblastoma. This molecular epidemiologic study proposes to use a case-control design, using questionnaires and blood samples, to examine two populations of mothers and children, one in central Mexico whose diet relies on foods not fortified with folate, and one in New York, where folate-fortified foods are widely consumed, in order to determine whether children with sporadic unilateral retinoblastoma and their mothers have an increased frequency of these MTHFR and MTRR mutations. The study will also examine whether the increased risk varies depending on folate intake, and levels of red blood cell and plasma folate, and plasma homocysteine. If our results are as anticipated, this project may lead to the development of new preventive strategies for those populations with an elevated incidence of sporadic retinoblastoma.
Funding Period: 2003-09-12 - 2009-08-31
more information: NIH RePORT

Top Publications

  1. pmc Validation of a novel method for retrospectively estimating nutrient intake during pregnancy using a semi-quantitative food frequency questionnaire
    Fabiola Mejía-Rodríguez
    Centro de Investigación en Nutrición y Salud, Instituto Nacional de Salud Pública INSP, Av Universidad 655, Santa María Ahuacatitlán Cerrada, Los Pinos y Caminera, 62508 Cuernavaca, Morelos, Mexico
    Matern Child Health J 16:1468-83. 2012
  2. pmc Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake
    Manuela A Orjuela
    Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA
    Cancer 118:5912-9. 2012
  3. pmc Validation of a food frequency questionnaire for retrospective estimation of diet during the first 2 years of life
    Fabiola Mejía-Rodríguez
    Centro de Investigación en Nutrición y Salud, Instituto Nacional de Salud Pública INSP, Av Universidad 655, 62100, Cuernavaca, Morelos, Mexico
    Matern Child Health J 18:268-85. 2014
  4. pmc Diagnostic delay and sociodemographic predictors of stage at diagnosis and mortality in unilateral and bilateral retinoblastoma
    Marco A Ramirez-Ortiz
    Authors Affiliations Departments of Ophthalmology, Pathology, and Oncology of the Hospital Infantil de Mexico Federico Gomez Hospital de Pediatria, Centro Medico Siglo XXI, Instituto Mexicano de Seguro Social, Mexico City, Mexico Departments of Biostatistics and Environmental Health Sciences and Pediatrics Division of Oncology, Columbia University, New York, New York
    Cancer Epidemiol Biomarkers Prev 23:784-92. 2014
  5. ncbi Fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma
    Manuela A Orjuela
    Department of Pediatrics, Mailman School of Public Health at Columbia University, Room B106, 60 Haven Avenue, New York, New York 10032, USA
    Cancer Epidemiol Biomarkers Prev 14:1433-40. 2005

Scientific Experts

  • Manuela Orjuela
  • Fabiola Mejía-Rodríguez
  • Marco A Ramirez-Ortiz
  • Armando García-Guerra
  • Lynnette M Neufeld
  • Xinhua Liu
  • M Veronica Ponce-Castaneda
  • M Lourdes Cabrera-Muñoz
  • Amado D Quezada-Sanchez
  • Aurora Medina-Sanson
  • Amado David Quezada-Sanchez

Detail Information

Publications5

  1. pmc Validation of a novel method for retrospectively estimating nutrient intake during pregnancy using a semi-quantitative food frequency questionnaire
    Fabiola Mejía-Rodríguez
    Centro de Investigación en Nutrición y Salud, Instituto Nacional de Salud Pública INSP, Av Universidad 655, Santa María Ahuacatitlán Cerrada, Los Pinos y Caminera, 62508 Cuernavaca, Morelos, Mexico
    Matern Child Health J 16:1468-83. 2012
    ..The FFQ-pregnancy provides a consistent estimate of maternal intake of key micronutrients during pregnancy and permits accurate ranking of intake 4-6 years post-partum...
  2. pmc Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake
    Manuela A Orjuela
    Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA
    Cancer 118:5912-9. 2012
    ..Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring...
  3. pmc Validation of a food frequency questionnaire for retrospective estimation of diet during the first 2 years of life
    Fabiola Mejía-Rodríguez
    Centro de Investigación en Nutrición y Salud, Instituto Nacional de Salud Pública INSP, Av Universidad 655, 62100, Cuernavaca, Morelos, Mexico
    Matern Child Health J 18:268-85. 2014
    ..05). The FFQ provides a reasonable estimate of a child's dietary intake of energy and key micronutrients during the second year of life, and permits accurate ranking of intake 3-5 years after birth. ..
  4. pmc Diagnostic delay and sociodemographic predictors of stage at diagnosis and mortality in unilateral and bilateral retinoblastoma
    Marco A Ramirez-Ortiz
    Authors Affiliations Departments of Ophthalmology, Pathology, and Oncology of the Hospital Infantil de Mexico Federico Gomez Hospital de Pediatria, Centro Medico Siglo XXI, Instituto Mexicano de Seguro Social, Mexico City, Mexico Departments of Biostatistics and Environmental Health Sciences and Pediatrics Division of Oncology, Columbia University, New York, New York
    Cancer Epidemiol Biomarkers Prev 23:784-92. 2014
    ..The relationship of diagnostic delay (lag time) and sociodemographic factors on the extent of disease at diagnosis has not been examined separately for unilateral and bilateral retinoblastoma...
  5. ncbi Fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma
    Manuela A Orjuela
    Department of Pediatrics, Mailman School of Public Health at Columbia University, Room B106, 60 Haven Avenue, New York, New York 10032, USA
    Cancer Epidemiol Biomarkers Prev 14:1433-40. 2005
    ..Fruits and vegetables are important sources of carotenoids and folate. We examined whether decreased gestational maternal intake of fruits and vegetables may contribute to development of sporadic retinoblastoma...