Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome
Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome
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DOI：
10.1158/0008-5472.can-08-3907
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Ellis, Ian O.
中科院分区：
文献类型：
--
作者：
Elsheikh, Somaia E.;Green, Andrew R.;Ellis, Ian O.
已知翻译后的组蛋白修饰在癌细胞中会发生改变，最近有研究表明，组蛋白乙酰化和甲基化标记的缺失可以预测人类癌症患者的预后。应用免疫组织化学方法检测880例乳腺癌组织中组蛋白赖氨酸乙酰化(H3L9ac、H3K18ac、H4K12ac和H4K16ac)、赖氨酸甲基化(H3K4me2和H4K20me3)和精氨酸甲基化(H4R3me2)标记。采用盲法半定量计分评估组织染色强度。使用免疫荧光染色和Western blotting进行验证研究。我们的分析显示，大多数乳腺癌患者(78.9%)H4K16ac水平降低或缺失，这表明这种改变可能是乳腺癌的早期迹象。组蛋白修饰状态、肿瘤生物标记物表型和临床结果之间存在高度显著的相关性，其中高相对水平的整体组蛋白乙酰化和甲基化与良好的预后相关，并且几乎只在管腔样乳腺肿瘤中检测到(93%)。中低水平的赖氨酸乙酰化(H3K9ac、H3K18ac和H4K12ac)、赖氨酸(H3K4me2和H4K20me3)和精氨酸甲基化(H4R3me2)在预后较差的亚型，包括基底细胞癌和HER-2阳性肿瘤中。聚类分析发现三组组蛋白在乳腺癌中表现出不同的模式，它们与已知的预后因素和临床结果有明显的关系。本研究发现组蛋白标记物在浸润性乳腺癌不同级别、不同形态类型和不同表型类别中的整体水平存在差异，并表明这些差异具有临床意义。[癌症资源2009；69(9)：3802-9]
Post-translational histone modifications are known to be altered in cancer cells, and loss of selected histone acetylation and methylation marks has recently been shown to predict patient outcome in human carcinoma. Immunohistochemistry was used to detect a series of histone lysine acetylation (H3L9ac, H3K18ac, H4K12ac, and H4K16ac), lysine methylation (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) marks in a well-characterized series of human breast carcinomas (n = 880). Tissue staining intensities were assessed using blinded semiquantitative scoring. Validation studies were done using immunofluorescence staining and Western blotting. Our analyses revealed low or absent H4K16ac in the majority of breast cancer cases (78.9%), suggesting that this alteration may represent an early sign of breast cancer. There was a highly significant correlation between histone modifications status, tumor biomarker phenotype, and clinical outcome, where high relative levels of global histone acetylation and methylation were associated with a favorable prognosis and detected almost exclusively in luminal-like breast tumors (93%). Moderate to low levels of lysine acetylation (H3K9ac, H3K18ac, and H4K12ac), lysine (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) were observed in carcinomas of poorer prognostic subtypes, including basal carcinomas and HER-2-positive tumors. Clustering analysis identified three groups of histone displaying distinct pattern in breast cancer, which have distinct relationships to known prognostic factors and clinical outcome. This study identifies the presence of variations in global levels of histone marks in different grades, morphologic types, and phenotype classes of invasive breast cancer and shows that these differences have clinical significance. [Cancer Res 2009;69(9):3802-9]