|Grant Number:||5R01CA098180-04 Interpret this number|
|Primary Investigator:||Orjuela, Manuela|
|Organization:||Columbia University Health Sciences|
|Project Title:||Folate Deficiency, Metabolism & Sporadic Retinoblastoma|
DESCRIPTION (provided by applicant): 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.
Overview of recurrent chromosomal losses in retinoblastoma detected by low coverage next generation sequencing.
Authors: García-Chequer A.J. , Méndez-Tenorio A. , Olguín-Ruiz G. , Sánchez-Vallejo C. , Isa P. , Arias C.F. , Torres J. , Hernández-Angeles A. , Ramírez-Ortiz M.A. , Lara C. , et al. .
Source: Cancer genetics, 2016 Mar; 209(3), p. 57-69.
EPub date: 2015-12-15.
Diagnostic delay and sociodemographic predictors of stage at diagnosis and mortality in unilateral and bilateral retinoblastoma.
Authors: Ramírez-Ortiz M.A. , Ponce-Castañeda M.V. , Cabrera-Muñoz M.L. , Medina-Sansón A. , Liu X. , Orjuela M.A. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2014 May; 23(5), p. 784-92.
EPub date: 2014-02-12.
Validation of a food frequency questionnaire for retrospective estimation of diet during the first 2 years of life.
Authors: Mejía-Rodríguez F. , Neufeld L.M. , García-Guerra A. , Quezada-Sanchez A.D. , Orjuela M.A. .
Source: Maternal and child health journal, 2014 Jan; 18(1), p. 268-85.
Validation of a novel method for retrospectively estimating nutrient intake during pregnancy using a semi-quantitative food frequency questionnaire.
Authors: Mejía-Rodríguez F. , Orjuela M.A. , García-Guerra A. , Quezada-Sanchez A.D. , Neufeld L.M. .
Source: Maternal and child health journal, 2012 Oct; 16(7), p. 1468-83.