Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
BMC Med Genomics. 2013 Sep 30;6:35. doi: 10.1186/1755-8794-6-35.
Alterations in epigenetic marks, including methylation or acetylation, are common in human cancers. For many epigenetic pathways, however, direct measures of activity are unknown, making their role in various cancers difficult to assess. Gene expression signatures facilitate the examination of patterns of epigenetic pathway activation across and within human cancer types allowing better understanding of the relationships between these pathways.
We used Bayesian regression to generate gene expression signatures from normal epithelial cells before and after epigenetic pathway activation. Signatures were applied to datasets from TCGA, GEO, CaArray, ArrayExpress, and the cancer cell line encyclopedia. For TCGA data, signature results were correlated with copy number variation and DNA methylation changes. GSEA was used to identify biologic pathways related to the signatures.
We developed and validated signatures reflecting downstream effects of enhancer of zeste homolog 2(EZH2), histone deacetylase(HDAC) 1, HDAC4, sirtuin 1(SIRT1), and DNA methyltransferase 2(DNMT2). By applying these signatures to data from cancer cell lines and tumors in large public repositories, we identify those cancers that have the highest and lowest activation of each of these pathways. Highest EZH2 activation is seen in neuroblastoma, hepatocellular carcinoma, small cell lung cancer, and melanoma, while highest HDAC activity is seen in pharyngeal cancer, kidney cancer, and pancreatic cancer. Across all datasets studied, activation of both EZH2 and HDAC4 is significantly underrepresented. Using breast cancer and glioblastoma as examples to examine intrinsic subtypes of particular cancers, EZH2 activation was highest in luminal breast cancers and proneural glioblastomas, while HDAC4 activation was highest in basal breast cancer and mesenchymal glioblastoma. EZH2 and HDAC4 activation are associated with particular chromosome abnormalities: EZH2 activation with aberrations in genes from the TGF and phosphatidylinositol pathways and HDAC4 activation with aberrations in inflammatory and chemokine related genes.
Gene expression patterns can reveal the activation level of epigenetic pathways. Epigenetic pathways define biologically relevant subsets of human cancers. EZH2 activation and HDAC4 activation correlate with growth factor signaling and inflammation, respectively, and represent two distinct states for cancer cells. This understanding may allow us to identify targetable drivers in these cancer subsets.
在人类癌症中，表观遗传标记（包括甲基化或乙酰化）的改变很常见。然而，对于许多表观遗传途径，其活性的直接测量方法尚不清楚，这使得评估它们在各种癌症中的作用变得困难。基因表达谱有助于检查跨人类癌症类型和内部的表观遗传途径激活模式，从而更好地理解这些途径之间的关系。
我们使用贝叶斯回归从正常上皮细胞在表观遗传途径激活前后生成基因表达谱。将这些特征应用于来自 TCGA、GEO、CaArray、ArrayExpress 和癌症细胞系百科全书的数据集。对于 TCGA 数据，特征结果与拷贝数变异和 DNA 甲基化变化相关联。使用 GSEA 来识别与特征相关的生物学途径。
我们开发并验证了反映增强子结合蛋白 2（EZH2）、组蛋白去乙酰化酶（HDAC）1、HDAC4、沉默调节蛋白 1（SIRT1）和 DNA 甲基转移酶 2（DNMT2）下游效应的特征。通过将这些特征应用于来自癌症细胞系和大型公共存储库中的肿瘤的数据，我们确定了这些癌症中每个途径的最高和最低激活。神经母细胞瘤、肝细胞癌、小细胞肺癌和黑色素瘤中 EZH2 激活最高，而咽癌、肾癌和胰腺癌中 HDAC 活性最高。在所研究的所有数据集上，EZH2 和 HDAC4 的激活都明显不足。以乳腺癌和神经胶质瘤为例，研究特定癌症的内在亚型，EZH2 激活在腔乳腺癌和神经前神经胶质瘤中最高，而 HDAC4 激活在基底乳腺癌和间充质神经胶质瘤中最高。EZH2 和 HDAC4 的激活与特定的染色体异常相关：EZH2 激活与 TGF 和磷脂酰肌醇途径的基因异常相关，而 HDAC4 激活与炎症和趋化因子相关基因的异常相关。
基因表达模式可以揭示表观遗传途径的激活水平。表观遗传途径定义了具有生物学意义的人类癌症亚群。EZH2 激活和 HDAC4 激活分别与生长因子信号和炎症相关，代表了癌细胞的两种不同状态。这种理解可能使我们能够识别这些癌症亚群中的可靶向驱动因素。
