Cargando…
Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia
BACKGROUND: There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953491/ https://www.ncbi.nlm.nih.gov/pubmed/29763473 http://dx.doi.org/10.1371/journal.pone.0197408 |
_version_ | 1783323366362447872 |
---|---|
author | Schraw, Jeremy M. Yiu, Teresa T. Lupo, Philip J. Tsavachidis, Spiridon Rau, Rachel Bondy, Melissa L. Rabin, Karen R. Shen, Lanlan Scheurer, Michael E. |
author_facet | Schraw, Jeremy M. Yiu, Teresa T. Lupo, Philip J. Tsavachidis, Spiridon Rau, Rachel Bondy, Melissa L. Rabin, Karen R. Shen, Lanlan Scheurer, Michael E. |
author_sort | Schraw, Jeremy M. |
collection | PubMed |
description | BACKGROUND: There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association. PROCEDURE: We obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors. Mothers of patients provided a saliva sample and were genotyped at 11 tagSNPs in MTR. DNA methylation was measured in bone marrow mononuclear cells of patients and six healthy marrow donors. We used hierarchical clustering to identify patients with a hypermethylator phenotype based on 281 differentially methylated promoter CpGs. We used logistic regression to estimate the effects of maternal genotype on the likelihood of DNA hypermethylation in ALL and Ingenuity Pathway Analysis to identify networks enriched for differentially methylated genes. RESULTS: Twenty-two cases (43%) demonstrated promoter hypermethylation, which was more frequent among those with ETV6-RUNX1 fusion and initial white blood cell count < 50 x 10(9)/L. Maternal rs12759827 was associated with aberrant DNA methylation (odds ratio [OR] 4.67, 95% confidence interval 1.46–16.31); non-significantly elevated ORs were observed for all other SNPs. Aberrantly methylated promoter CpGs aligned to genes with known cancer-related functions. DISCUSSION: Maternal folate metabolic genotype may be associated with DNA methylation patterns in ALL in their offspring. Therefore, the effect of maternal genotypes on ALL susceptibility may act through aberrant promoter methylation, which may contribute to the in utero origins of ALL. |
format | Online Article Text |
id | pubmed-5953491 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-59534912018-05-25 Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia Schraw, Jeremy M. Yiu, Teresa T. Lupo, Philip J. Tsavachidis, Spiridon Rau, Rachel Bondy, Melissa L. Rabin, Karen R. Shen, Lanlan Scheurer, Michael E. PLoS One Research Article BACKGROUND: There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association. PROCEDURE: We obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors. Mothers of patients provided a saliva sample and were genotyped at 11 tagSNPs in MTR. DNA methylation was measured in bone marrow mononuclear cells of patients and six healthy marrow donors. We used hierarchical clustering to identify patients with a hypermethylator phenotype based on 281 differentially methylated promoter CpGs. We used logistic regression to estimate the effects of maternal genotype on the likelihood of DNA hypermethylation in ALL and Ingenuity Pathway Analysis to identify networks enriched for differentially methylated genes. RESULTS: Twenty-two cases (43%) demonstrated promoter hypermethylation, which was more frequent among those with ETV6-RUNX1 fusion and initial white blood cell count < 50 x 10(9)/L. Maternal rs12759827 was associated with aberrant DNA methylation (odds ratio [OR] 4.67, 95% confidence interval 1.46–16.31); non-significantly elevated ORs were observed for all other SNPs. Aberrantly methylated promoter CpGs aligned to genes with known cancer-related functions. DISCUSSION: Maternal folate metabolic genotype may be associated with DNA methylation patterns in ALL in their offspring. Therefore, the effect of maternal genotypes on ALL susceptibility may act through aberrant promoter methylation, which may contribute to the in utero origins of ALL. Public Library of Science 2018-05-15 /pmc/articles/PMC5953491/ /pubmed/29763473 http://dx.doi.org/10.1371/journal.pone.0197408 Text en © 2018 Schraw et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Schraw, Jeremy M. Yiu, Teresa T. Lupo, Philip J. Tsavachidis, Spiridon Rau, Rachel Bondy, Melissa L. Rabin, Karen R. Shen, Lanlan Scheurer, Michael E. Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia |
title | Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia |
title_full | Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia |
title_fullStr | Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia |
title_full_unstemmed | Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia |
title_short | Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia |
title_sort | maternal folate genes and aberrant dna hypermethylation in pediatric acute lymphoblastic leukemia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953491/ https://www.ncbi.nlm.nih.gov/pubmed/29763473 http://dx.doi.org/10.1371/journal.pone.0197408 |
work_keys_str_mv | AT schrawjeremym maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia AT yiuteresat maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia AT lupophilipj maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia AT tsavachidisspiridon maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia AT raurachel maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia AT bondymelissal maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia AT rabinkarenr maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia AT shenlanlan maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia AT scheurermichaele maternalfolategenesandaberrantdnahypermethylationinpediatricacutelymphoblasticleukemia |