Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation
Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation
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DOI：
10.1158/0008-5472.can-06-1547
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Costello, Joseph F.
中科院分区：
文献类型：
--
作者：
Cadieux, Benoit;Ching, Tsui-Ting;Costello, Joseph F.
全基因组5-甲基胞嘧啶的减少是人类肿瘤发生的表观遗传标志。实验诱导的小鼠低甲基化促进了基因组的不稳定性，并足以启动肿瘤发生。在这里，我们报告了整体低甲基化在原发性人类胶质母细胞瘤[多形性胶质母细胞瘤（GBM）]中很常见，并且可以影响每个单倍体肿瘤基因组估计多达1000万个CpG二核苷酸。去甲基化涉及1号和16号染色体上的卫星2 （Sat2）中心粒DNA， 4q和10q染色体上的亚端粒重复序列D4Z4，以及散布的AIu元件。严重的Sat2序列低甲基化与邻近的常染色质拷贝数改变有关，这表明低甲基化可能是GBMs中常见的特异性遗传改变的一个易感性因素。整体低甲基化的另一个明显后果是通过启动子去甲基化重新激活癌睾丸抗原MAGEA1，但仅在GBMs和GBM细胞系中表现出5-甲基胞嘧啶含量低于50%的阈值。具有显著低甲基化的原发性GBMs倾向于与限制性甲基代谢基因亚甲基四氢叶酸还原酶（MTHFR）的低功能Val等位基因杂合或纯合，或者在1p36处缺失该基因。基因组低甲基化严重的肿瘤也有增殖指数升高和MTHFR基因缺失。这些数据表明，在MTHFR缺乏导致甲基供体产生不足的情况下，细胞过度增殖会促进基因组低甲基化和进一步的基因组不稳定，或者MTHFR缺乏相关的去甲基化会导致GBM的增殖活性增加。
Genome-wide reduction in 5-methylcytosine is an epigenetic hallmark of human tumorigenesis. Experimentally induced hypomethylation in mice promotes genomic instability and is sufficient to initiate tumorigenesis. Here, we report that global hypomethylation is common in primary human glioblastomas [glioblastoma multiforme (GBM)] and can affect up to an estimated 10 million CpG dinucleotides per haploid tumor genome. Demethylation involves satellite 2 (Sat2) pericentromeric DNA at chromosomes 1 and 16, the subtelomeric repeat sequence D4Z4 at chromosomes 4q and 10q, and interspersed AIu elements. Severe hypornethylation of Sat2 sequences is associated with copy number alterations of the adjacent euchromatin, suggesting that hypornethylation may be one factor predisposing to specific genetic alterations commonly occurring in GBMs. An additional apparent consequence of global hypomethylation is reactivation of the cancer-testis antigen MAGEA1 via promoter demethylation, but only in GBMs and GBM cell lines exhibiting a 5-methylcytosine content below a threshold of similar to 50%. Primary GBMs with significant hypomethylation tended to be heterozygous or homozygous for the low-functioning Val allele of the rate-limiting methyl group metabolism gene methylenetetrahydrofolate reductase (MTHFR), or had a deletion encompassing this gene at 1p36. Tumors with severe genomic hypomethylation also had an elevated proliferation index and deletion of the MTHFR gene. These data suggest a model whereby either excessive cell proliferation in the context of inadequate methyl donor production from MTHFR deficiency promotes genomic hypornethylation and further genomic instability, or that MTHFR deficiency-associated demethylation leads to increased proliferative activity in GBM.