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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >Histone-modifier gene expression profiles are associated with pathological and clinical outcomes in human breast cancer.
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Histone-modifier gene expression profiles are associated with pathological and clinical outcomes in human breast cancer.

机译：组蛋白修饰基因表达谱与人类乳腺癌的病理和临床结局有关。

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摘要

BACKGROUND: Epigenetic regulation of gene expression is under normal circumstances tightly controlled by the specific methylation of cytosine residues in CpG dinucleotides and coordinated by adjustments in the histone-dependent configuration of chromatin. Following our original report, providing the first description of potential tumor suppressor function associated with the histone methyltransferase SET domain containing 2 (SETD2) in breast cancer, the objective of this study was to determine the expression profiles of 16 further histone-modifier genes in a well annotated cohort of patients with primary operable breast cancer. MATERIALS AND METHODS: Breast cancer tissues (n=127) and normal tissues (n=33) underwent RNA extraction and reverse transcription, and histone-modifier gene transcript levels were determined using real-time quantitative PCR. The histone-modifier genes included: histone acetyltransferases (cAMP response element-binding protein-binding protein (CREBBP)); class I (histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2)), II (histone deacetylase 5 (HDAC5)) and III (sirtuin 1 (SIRT1)) histone deacetylases; and histone methyltransferases (SET domain containing suppressor of variegation 3-9 homolog 1 (SUV39H1) and suppressor of variegation 3-9 homolog 2 (SUV39H2)) amongst others. Expression levels were analysed against tumor size, grade, nodal involvement, histological subtype, receptor status, TNM stage, Nottingham Prognostic Index, and disease-free and overall survival over a 10-year follow-up period. RESULTS: Expression of histone-modifier genes in breast cancer differed significantly from those in normal tissue (HDAC5, HDAC1, lysine (K)-specific demethylase 4A (KDM4A) and lysine (K)-specific demethylase 6A (KDM6A)). Differences in expression profiles were also found to exist between individual breast tumors and, in some cases, were significantly associated with conventional pathological parameters and prognostic indices: tumor grade (K (lysine) acetyltransferase 5 (KAT5), HDAC1, KDM4A, SUV39H1 and KDM6A)); TNM stage (SUV39H1, K (lysine) acetyltransferase 2B (KAT2B), lysine (K)-specific demethylase 1A (KDM1A), KDM4A, lysine (K)-specific demethylase 5C (KDM5C), K (lysine) acetyltransferase 8 (KAT8), HDAC5 and KAT5)); Nottingham Prognostic Index (KDM5C, myeloid/lymphoid or mixed-lineage leukemia (MLL), KAT8 and SET and MYND domain containing 3 (SMYD3)); receptor status (KAT5, SMYD3 and KDM1A); histological type (KAT5, KDM5C, KAT8, KDM4A and MLL); disease-free survival (SUV39H1, SMYD3, HDAC5, KDM6A, HDAC1, KDM1A, KDM4A, KAT8, KDM5C, KAT5 and MLL) and overall survival (KAT8). Significant correlations were identified between the differential expression profiles of particular histone-modifying genes. CONCLUSION: Expression levels of histone-modifier genes in breast cancer differ significantly from normal tissue. Differences in expression profiles exist between breast tumors and are significantly associated with conventional pathological parameters and clinical outcomes. Further study is warranted to determine the consequences of altered expression for each specific histone-modifier gene and the biological and clinical implications of combinatorial variations in expression profiles. Histone-modifier enzymes offer utility as biomarkers and potential for targeted therapeutic strategies.
机译：背景：在正常情况下，基因表达的表观遗传调控受到CpG二核苷酸胞嘧啶残基的特异性甲基化的严格控制，并受到染色质依赖组蛋白的构型的调节。继我们的原始报告之后，首次提供了与乳腺癌中含有2（SETD2）的组蛋白甲基转移酶SET结构域相关的潜在肿瘤抑制功能的描述，本研究的目的是确定16种其他组蛋白修饰基因在乳腺癌中的表达谱。具有良好注释的原发性可手术乳腺癌患者队列。材料与方法：乳腺癌组织（n = 127）和正常组织（n = 33）进行RNA提取和逆转录，并使用实时定量PCR测定组蛋白修饰基因的转录水平。组蛋白修饰基因包括：组蛋白乙酰转移酶（cAMP反应元件结合蛋白结合蛋白（CREBBP））; I类（组蛋白脱乙酰基酶1（HDAC1）和组蛋白脱乙酰基酶2（HDAC2）），II（组蛋白脱乙酰基酶5（HDAC5））和III（组蛋白1（SIRT1））组蛋白脱乙酰基酶;以及组蛋白甲基转移酶（SET结构域包含3-9同源物1的抑制物（SUV39H1）和3-9同源物2的抑制物（SUV39H2））等。针对肿瘤大小，等级，淋巴结受累，组织学亚型，受体状态，TNM分期，诺丁汉预后指数以及10年随访期的无病生存期和总生存期，分析表达水平。结果：组蛋白修饰基因在乳腺癌中的表达与正常组织中的显着不同（HDAC5，HDAC1，赖氨酸（K）特异性脱甲基酶4A（KDM4A）和赖氨酸（K）特异性脱甲基酶6A（KDM6A））。在各个乳腺肿瘤之间也存在表达谱差异，并且在某些情况下与常规病理参数和预后指标显着相关：肿瘤等级（K（赖氨酸）乙酰基转移酶5（KAT5），HDAC1，KDM4A，SUV39H1和KDM6A ））; TNM期（SUV39H1，K（赖氨酸）乙酰转移酶2B（KAT2B），赖氨酸（K）特异性脱甲基酶1A（KDM1A），KDM4A，赖氨酸（K）特异性脱甲基酶5C（KDM​​5C），K（赖氨酸）乙酰转移酶8（KAT8） ，HDAC5和KAT5））;诺丁汉预后指数（KDM5C，髓样/淋巴样或混合谱系白血病（MLL），KAT8和SET以及含有3的MYND域（SMYD3））;受体状态（KAT5，SMYD3和KDM1A）;组织学类型（KAT5，KDM5C，KAT8，KDM4A和MLL）;无病生存期（SUV39H1，SMYD3，HDAC5，KDM6A，HDAC1，KDM1A，KDM4A，KAT8，KDM5C，KAT5和MLL）和整体生存期（KAT8）。在特定的组蛋白修饰基因的差异表达谱之间鉴定出显着的相关性。结论：乳腺癌中组蛋白修饰基因的表达水平与正常组织有显着差异。乳腺肿瘤之间存在表达谱差异，并且与常规病理参数和临床结果显着相关。有必要进行进一步的研究以确定每种特定的组蛋白修饰基因的表达改变的后果，以及表达谱中组合变异的生物学和临床意义。组蛋白修饰酶可作为生物标志物使用，并具有针对性治疗策略的潜力。

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