Integrative genomic and transcriptomic analysis for pinpointing recurrent alterations of plant homeodomain genes and their clinical significance in breast cancer.
Integrative genomic and transcriptomic analysis for pinpointing recurrent alterations of plant homeodomain genes and their clinical significance in breast cancer.
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DOI：
10.18632/oncotarget.14402
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发表时间：
2017-02-21
期刊：
影响因子：
--
通讯作者：
Yang ZQ
中科院分区：
文献类型：
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作者：
Yu H;Jiang Y;Liu L;Shan W;Chu X;Yang Z;Yang ZQ
调节染色质修饰、基因表达、基因组稳定性和 DNA 修复的多种表观遗传效应子均包含结构保守的结构域，称为植物同源结构域 (PHD) 指。由于基因组扩增、突变、缺失和易位而导致的几种 PHD 含指蛋白 (PHF) 的改变与各种类型的癌症直接相关。然而，人们对 PHF 在乳腺癌中的基因组景观和临床意义知之甚少。因此，我们使用 TCGA 和 METABRIC 数据集对乳腺癌中的 98 个 PHF 基因进行了大规模基因组和转录组分析，并将反复发生的改变与患者的临床病理特征和生存相关联。不同亚型的乳腺癌对于每种 PHF 具有不同的拷贝数和表达模式。我们鉴定了 PHF 基因的子集，这些基因经常发生高频率改变，包括 PYGO2（尾足家族 PHD 指 2）、ZMYND8（锌指，MYND 型包含 8 个）、ASXL1（附加性梳如 1）和 CHD3（染色质结构域解旋酶 DNA 结合蛋白 3）。 ZMYND8 拷贝数增加和过度表达在 Luminal B 亚型中更为普遍，并且与乳腺癌患者的较短生存期显着相关。 ZMYND8 还参与雌激素受体 (ER) 途径的正反馈回路，并且 ZMYND8 在乳腺癌中的表达受到溴结构域和额外末端 (BET) 抑制剂的抑制。我们的研究结果为未来的研究提供了一条有希望的途径——专注于 PHF 的一个子集，以更好地了解分子机制并确定乳腺癌的治疗靶点。
A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of patients. Different subtypes of breast cancer had different patterns of copy number and expression for each PHF. We identified a subset of PHF genes that was recurrently altered with high prevalence, including PYGO2 (pygopus family PHD finger 2), ZMYND8 (zinc finger, MYND-type containing 8), ASXL1 (additional sex combs like 1) and CHD3 (chromodomain helicase DNA binding protein 3). Copy number increase and overexpression of ZMYND8 were more prevalent in Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. ZMYND8 was also involved in a positive feedback circuit of the estrogen receptor (ER) pathway, and the expression of ZMYND8 was repressed by the bromodomain and extra terminal (BET) inhibitor in breast cancer. Our findings suggest a promising avenue for future research—to focus on a subset of PHFs to better understand the molecular mechanisms and to identify therapeutic targets in breast cancer.