Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia.
Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia.
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DOI：
10.1371/journal.pone.0197408
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Scheurer ME
中科院分区：
文献类型：
--
作者：
Schraw JM;Yiu TT;Lupo PJ;Tsavachidis S;Rau R;Bondy ML;Rabin KR;Shen L;Scheurer ME
有证据表明，母亲的叶酸相关基因的基因型与儿童急性淋巴细胞白血病（ALL）独立的后代基因型。我们评估了母亲甲硫氨酸合酶（MTR）基因型与ALL DNA甲基化状态之间的关系，以更好地描述这种关联的分子机制。我们从51名ALL患者和6名健康供体中获得了骨髓样本。患者的母亲提供唾液样本，并在MTR中的11个tagSNPs进行基因分型。在患者和6名健康骨髓供体的骨髓单个核细胞中测量DNA甲基化。我们使用分层聚类，以确定基于281个差异甲基化启动子CpG的高甲基化表型的患者。我们使用逻辑回归来估计母亲基因型对ALL中DNA高甲基化可能性的影响，并使用免疫途径分析来识别富含差异甲基化基因的网络。22例（43%）显示启动子高甲基化，在ETV 6-RUNX 1融合和初始白色血细胞计数< 50 x 109/L的患者中更常见。母亲rs 12759827与异常DNA甲基化相关（比值比[OR] 4.67，95%置信区间1.46-16.31）;观察到所有其他SNP的OR无显著升高。异常甲基化的启动子CpG与已知癌症相关功能的基因对齐。母亲叶酸代谢基因型可能与其后代ALL的DNA甲基化模式相关。因此，母亲基因型对ALL易感性的影响可能通过异常启动子甲基化起作用，这可能有助于ALL的宫内起源。
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. 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. 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 109/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. 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.
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影响因子：
--
作者：
Wang H;Wang J;Zhao L;Liu X;Mi W
通讯作者：
Mi W
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
2.3
作者：
Lupo, Philip J.;Nousome, Darryl;Kamdar, Kala Y.;Okcu, M. Fatih;Scheurer, Michael E.
通讯作者：
Scheurer, Michael E.
影响因子：
168.9
作者：
Wiemels, JL;Cazzaniga, G;Greaves, MF
通讯作者：
Greaves, MF
影响因子：
82.9
作者：
MERLO, A;HERMAN, JG;SIDRANSKY, D
通讯作者：
SIDRANSKY, D