Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.
Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.
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DOI：
10.18632/oncotarget.2967
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发表时间：
2015-02-10
期刊：
影响因子：
--
通讯作者：
Yang ZQ
中科院分区：
文献类型：
--
作者：
Liu L;Kimball S;Liu H;Holowatyj A;Yang ZQ
组蛋白赖氨酸甲基转移酶 (HMT) 是一大类催化组蛋白和其他蛋白质上赖氨酸残基位点特异性甲基化的酶，在控制转录、染色质结构和细胞分化中发挥着关键作用。然而，HMT 在乳腺癌中的基因组图谱和临床意义仍然知之甚少。在这里，我们对乳腺癌中大约 50 个 HMT 进行了荟萃分析，并确定了复发性拷贝数改变、突变、基因表达和临床结果之间的关联。我们鉴定了 12 个遗传改变频率最高的 HMT，其中 8 个具有高水平扩增，2 个具有假定的纯合缺失，2 个具有体细胞突变。不同亚型的乳腺癌具有不同的 HMT 基因拷贝数和表达模式。此外，1q 染色体包含四个 HMT，它们在乳腺癌中同时或独立扩增或过度表达。几种 HMT 的拷贝数或 mRNA 表达与基底样乳腺癌和较短的患者生存期显着相关。综合分析确定了 8 个因基因改变而失调的 HMT（SETDB1、SMYD3、ASH1L、SMYD2、WHSC1L1、SUV420H1、SETDB2 和 KMT2C），将它们归类为候选治疗靶点。总之，我们的研究结果为使用 HMT 治疗乳腺癌的进一步机制研究和治疗选择奠定了坚实的基础。
Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome. We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation. Different subtypes of breast cancer have different patterns of copy number and expression for each HMT gene. In addition, chromosome 1q contains four HMTs that are concurrently or independently amplified or overexpressed in breast cancer. Copy number or mRNA expression of several HMTs was significantly associated with basal-like breast cancer and shorter patient survival. Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets. Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer.
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