Microsatellite instability in pediatric high grade glioma is associated with genomic profile and differential target gene inactivation.
Microsatellite instability in pediatric high grade glioma is associated with genomic profile and differential target gene inactivation.
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DOI：
10.1371/journal.pone.0020588
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Reis RM
中科院分区：
文献类型：
--
作者：
Viana-Pereira M;Lee A;Popov S;Bax DA;Al-Sarraj S;Bridges LR;Stávale JN;Hargrave D;Jones C;Reis RM
高级别胶质瘤 (HGG) 是儿童癌症相关死亡的主要原因之一，越来越多的证据表明，与成人肿瘤相比，儿童 HGG 可能具有独特的分子特征。我们试图阐明微卫星不稳定性 (MSI) 在儿童与成人 HGG 中的作用。使用一组完善的五种准单态单核苷酸重复标记物确定了 144 名患者（71 名儿童和 73 名成人）的 MSI 状态。通过免疫组织化学测定 MLH1、MSH2、MSH6 和 PMS2 的表达，通过直接测序和使用 MS-PCR 启动子甲基化评估 MLH1 的突变。使用阵列 CGH 得出 DNA 拷贝数谱，并通过多重 PCR 和基因分型研究 18 个 MSI 靶基因的突变。 14/71 (19.7%) 儿童病例中发现 MSI，显着高于成人病例 (5/73，6.8%；p = 0.02，卡方检验)。 10/13 的病例中 MLH1 表达下调，但未发现突变或启动子甲基化。一种儿童 MSI 高肿瘤中不存在 MSH6，这与与种系 MSH6 突变相关的遗传性错配修复缺陷一致。 MSI 被归类为 A 型，并与非常稳定的基因组图谱相关。在 18 个经典 MSI 靶基因中，我们仅鉴定了 MSH6 和 DNAPKcs 中的突变，并描述了 MRE11 中的多态性，在 DNA 双链断裂检测和修复中没有明显的功能后果。因此，这项研究为部分神经胶质瘤中与 MSI 存在相关的潜在新分子途径提供了证据。
High grade gliomas (HGG) are one of the leading causes of cancer-related deaths in children, and there is increasing evidence that pediatric HGG may harbor distinct molecular characteristics compared to adult tumors. We have sought to clarify the role of microsatellite instability (MSI) in pediatric versus adult HGG. MSI status was determined in 144 patients (71 pediatric and 73 adults) using a well established panel of five quasimonomorphic mononucleotide repeat markers. Expression of MLH1, MSH2, MSH6 and PMS2 was determined by immunohistochemistry, MLH1 was assessed for mutations by direct sequencing and promoter methylation using MS-PCR. DNA copy number profiles were derived using array CGH, and mutations in eighteen MSI target genes studied by multiplex PCR and genotyping. MSI was found in 14/71 (19.7%) pediatric cases, significantly more than observed in adults (5/73, 6.8%; p = 0.02, Chi-square test). MLH1 expression was downregulated in 10/13 cases, however no mutations or promoter methylation were found. MSH6 was absent in one pediatric MSI-High tumor, consistent with an inherited mismatch repair deficiency associated with germline MSH6 mutation. MSI was classed as Type A, and associated with a remarkably stable genomic profile. Of the eighteen classic MSI target genes, we identified mutations only in MSH6 and DNAPKcs and described a polymorphism in MRE11 without apparent functional consequences in DNA double strand break detection and repair. This study thus provides evidence for a potential novel molecular pathway in a proportion of gliomas associated with the presence of MSI.