Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America.
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS One. 2018 May 15;13(5):e0197408. doi: 10.1371/journal.pone.0197408. eCollection 2018.
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.
有证据表明，叶酸相关基因中的母体基因型与儿童急性淋巴细胞白血病（ALL）独立于后代基因型有关。我们评估了亚甲基四氢叶酸还原酶（MTR）中母体基因型与 ALL 中 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。
我们在诊断时从 51 名 ALL 患者和 6 名健康供体中获得了骨髓样本。患者的母亲提供了唾液样本，并在 MTR 中 11 个标签 SNP 上进行了基因分型。我们在患者和 6 名健康骨髓供体的骨髓单核细胞中测量了 DNA 甲基化。我们使用层次聚类根据 281 个差异甲基化启动子 CpG 来识别具有高甲基化表型的患者。我们使用逻辑回归来估计母体基因型对 ALL 中 DNA 高甲基化的可能性的影响，并使用 Ingenuity 通路分析来识别差异甲基化基因富集的网络。
22 例（43%）表现出启动子过度甲基化，其中 ETV6-RUNX1 融合和初始白细胞计数<50×109/L 的患者更为常见。母体 rs12759827 与异常 DNA 甲基化相关（比值比[OR]4.67，95%置信区间 1.46-16.31）；所有其他 SNP 观察到的 OR 均升高不显著。异常甲基化的启动子 CpG 与具有已知癌症相关功能的基因对齐。
母体叶酸代谢基因型可能与后代 ALL 中的 DNA 甲基化模式相关。因此，母体基因型对 ALL 易感性的影响可能通过异常启动子甲基化起作用，这可能导致 ALL 的宫内起源。
