Grant Details
Grant Number: |
1R01CA192662-01A1 Interpret this number |
Primary Investigator: |
Orjuela, Manuela |
Organization: |
Columbia University Health Sciences |
Project Title: |
Methylation and Mutations in Rb1 and Variants of Synthetic Folic Acid Metabolism |
Fiscal Year: |
2015 |
Abstract
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DESCRIPTION (provided by applicant): Synthetic folic acid supplements are consumed by 50% of US adults. High folic acid intake can result in CpG island hypermethylation. Recent studies suggest high intake may contribute to carcinogenesis particularly in those persons unable to metabolize folic acid efficiently such as persons homozygous for the 19bp deletion polymorphism in the dihydrofolate reductase(DHFR) gene (rs70991108). Homozygotes (19% of US adults) have less efficient conversion of synthetic folic acid into biological folate. Women homozygous for the DHFR19bp deletion (DHFR19bpdel) are at increased risk for having a child with retinoblastoma, a neuro-ectodermally derived early childhood cancer that has served as a model for understanding carcinogenesis. This risk appears elevated among women homozygous for DHFR19bpdel who consumed folic acid containing prenatal supplements in the first trimester. In retinoblastoma, 37% of disease-causing mutations in the CpG-rich gene, RB1, are due to deamination of methylated cytosines in RB1, while an additional 12% are caused by methylation of the RB1 promoter. We hypothesize that these methylation related RB1-inactivating changes may be induced by less functional genetic variations in folate metabolism and excess exposure in early retinal development. Murine models suggest particular sensitivity to folic acid exposure in early neural development. In humans, periods of dietary inadequacy in early gestation are associated with hyper-methylation at meta- stable epialleles. Pilot data from mutation assays and methylation arrays from our ongoing case-series study of newly diagnosed retinoblastoma (mean age 23 months) in Central Mexico, EpiRbMx, suggest that women who have the less efficient DHFR 19bpdel and high folic acid prenatally have higher risk of a child with a methylation related RB1-inactivating mutation or differentially hyper-methylated RB1 promoter directly resulting in tumor formation. Maternal DHFR19bpdel homozygosity combined with high prenatal folic acid intake may lead to RB1 hyper-methylation in developmentally susceptible cells, thereby contributing to carcinogenesis. Based on the results of our pilot data, we propose to use existing samples and data from 337 cases in our ongoing EpiRbMx study (founded in 2003) including pre-treatment measures of mother and child plasma nutrients, diet intake, genotype, and tumors, to test our hypothesis of an association between maternal DHFR 19bpdel and prenatal folic acid exposure (using plasma and intake measures) and 1) methylation related RB1 mutations, specifically in somatic (non-germline) RB1 mutations, and 2) methylation of the RB1 promoter. We will further examine the impact of DHFR and prenatal folic acid exposure on differential methylation in metastable epialleles to document their
effect on the developing epigenome. Given the high frequency of RB1 mutations among poor prognosis adult tumors such as small cell lung cancer(54%) or glioblastoma(11%) and the high proportion (19%) of adults with less efficient folic acid metabolism, the potential translational impact of our study is high, as our results can inform public health policy and evaluation of synthetic folic acid exposure.
Publications
Childhood Cancer Death When Life Transpires Where High Childhood Poverty Has Persisted for Decades.
Authors: Orjuela-Grimm M.A.
, Beauchemin M.P.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2023-03-06 00:00:00.0; 32(3), p. 295-297.
PMID: 36872901
Related Citations
Association between Predictors of Vitamin D Serum Levels and Risk of Retinoblastoma in Children: A Case-Control Study.
Authors: Mejía-Rodríguez F.
, Flores-Aldana M.E.
, Quezada-Sánchez A.D.
, Shamah-Levy T.
, Villalpando S.
, Contreras-Manzano A.
, Bhatt-Carreño S.
, Orjuela-Grimm M.
.
Source: Nutrients, 2021-07-23 00:00:00.0; 13(8), .
EPub date: 2021-07-23 00:00:00.0.
PMID: 34444670
Related Citations
Sunlight exposure in infancy decreases risk of sporadic retinoblastoma, extent of intraocular disease.
Authors: Orjuela-Grimm M.
, Carreño S.B.
, Liu X.
, Ruiz A.
, Medina P.
, Ramirez Ortiz M.A.
, Rendon J.R.
, Molina N.C.L.
, Pinilla H.
, Hinojosa D.
, et al.
.
Source: Cancer Reports (hoboken, N.j.), 2021-05-07 00:00:00.0; , p. e1409.
EPub date: 2021-05-07 00:00:00.0.
PMID: 33960746
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Joining Efforts for PTLD: Lessons Learned from Comparing the Approach and Treatment Strategies Across the Pediatric and Adult Age Spectra.
Authors: Montanari F.
, Orjuela-Grimm M.
.
Source: Current Hematologic Malignancy Reports, 2021 Feb; 16(1), p. 52-60.
EPub date: 2021-02-05 00:00:00.0.
PMID: 33544319
Related Citations
COVID-19 disease in New York City pediatric hematology and oncology patients.
Authors: Gampel B.
, Troullioud Lucas A.G.
, Broglie L.
, Gartrell-Corrado R.D.
, Lee M.T.
, Levine J.
, Orjuela-Grimm M.
, Satwani P.
, Glade-Bender J.
, Roberts S.S.
.
Source: Pediatric Blood & Cancer, 2020 Sep; 67(9), p. e28420.
EPub date: 2020-06-26 00:00:00.0.
PMID: 32588957
Related Citations
Discovery of a transcriptomic core of genes shared in 8 primary retinoblastoma with a novel detection score analysis.
Authors: Alvarez-Suarez D.E.
, Tovar H.
, Hernández-Lemus E.
, Orjuela M.
, Sadowinski-Pine S.
, Cabrera-Muñoz L.
, Camacho J.
, Favari L.
, Hernández-Angeles A.
, Ponce-Castañeda M.V.
.
Source: Journal Of Cancer Research And Clinical Oncology, 2020-05-30 00:00:00.0; , .
EPub date: 2020-05-30 00:00:00.0.
PMID: 32474753
Related Citations
Fortification of bakery and corn masa-based foods in Mexico and dietary intake of folic acid and folate in Mexican national survey data.
Authors: Orjuela M.A.
, Mejia-Rodriguez F.
, Quezada A.D.
, Sanchez-Pimienta T.G.
, Shamah-Levy T.
, Romero-Rendón J.
, Bhatt-Carreño S.
, Ponce-Castañeda M.V.
, Castro M.A.
, Paul L.
, et al.
.
Source: The American Journal Of Clinical Nutrition, 2019-12-01 00:00:00.0; 110(6), p. 1434-1448.
PMID: 31529037
Related Citations
miRNome landscape analysis reveals a 30 miRNA core in retinoblastoma.
Authors: Castro-Magdonel B.E.
, Orjuela M.
, Camacho J.
, García-Chéquer A.J.
, Cabrera-Muñoz L.
, Sadowinski-Pine S.
, Durán-Figueroa N.
, Orozco-Romero M.J.
, Velázquez-Wong A.C.
, Hernández-Ángeles A.
, et al.
.
Source: Bmc Cancer, 2017-07-01 00:00:00.0; 17(1), p. 458.
EPub date: 2017-07-01 00:00:00.0.
PMID: 28668075
Related Citations
Socioeconomic Status And Global Variations In The Incidence Of Neuroblastoma: Call For Support Of Population-based Cancer Registries In Low-middle-income Countries
Authors: Kamihara J.
, Ma C.
, Fuentes Alabi S.L.
, Garrido C.
, Frazier A.L.
, Rodriguez-Galindo C.
, Orjuela M.A.
.
Source: Pediatric Blood & Cancer, 2017 Feb; 64(2), p. 321-323.
PMID: 27734570
Related Citations
Dietary intake and childhood leukemia: The Diet and Acute Lymphoblastic Leukemia Treatment (DALLT) cohort study.
Authors: Ladas E.J.
, Orjuela M.
, Stevenson K.
, Cole P.D.
, Lin M.
, Athale U.H.
, Clavell L.A.
, Leclerc J.M.
, Michon B.
, Schorin M.A.
, et al.
.
Source: Nutrition (burbank, Los Angeles County, Calif.), 2016 Oct; 32(10), p. 1103-1109.e1.
EPub date: 2016-03-28 00:00:00.0.
PMID: 27318855
Related Citations
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.
PMID: 26883451
Related Citations
Illumina next generation sequencing data and expression microarrays data from retinoblastoma and medulloblastoma tissues.
Authors: García-Chequer A.J.
, Méndez-Tenorio A.
, Olguín-López G.
, Sánchez-Vallejo C.
, Isa P.
, Arias C.F.
, Torres J.
, Hernández-Angeles A.
, Ramírez-Ortiz M.A.
, Lara C.
, et al.
.
Source: Data In Brief, 2016 Mar; 6, p. 908-16.
PMID: 26937470
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