Constitutive expression of γ-H2AX has prognostic relevance in triple negative breast cancer
Constitutive expression of γ-H2AX has prognostic relevance in triple negative breast cancer
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DOI：
10.1016/j.radonc.2011.07.009
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发表时间：
2011-10-01
影响因子：
5.7
通讯作者：
Span, Paul N.
中科院分区：
文献类型：
--
作者：
Nagelkerke, Anika;van Kuijk, Simon J. A.;Span, Paul N.
背景和目的：结构性的伽马-H_2AX表达可能意味着DNA损伤修复途径的中断、基因组的不稳定或端粒末端的缩短。在此，我们定量检测了大量乳腺癌细胞系(n=54)和一组未接受系统辅助治疗的结节阴性乳腺癌(n=122)中内源性γ-H_2AX及其下游因子53BP1的表达。材料和方法：采用免疫组织化学方法检测乳腺癌细胞系和肿瘤组织中γ-H_2AX和53BP1的表达，并分析其与细胞系、患者和肿瘤特征以及疾病进展的关系。结果：在乳腺癌细胞系中，γ-H_2AX阳性与三重阴性/基础样亚组相关(p=0.005)。BRCA1(p=0.011)或P53(p=0.053)突变。具体地说，在三阴性乳腺癌患者中，伽马-H_2AX病灶数目越多，预后越差(三阴性患者P=0.006，而雌激素受体(ER)、孕激素受体(PR)或HER_2阳性患者P=0.417)。53BP1与疾病进展也有类似的关联。在肿瘤大小、分级和三重阴性的多因素分析中，只有三重阴性与伽马-H_2AX的交互作用仍然显著(p=0.002，危险比=6.77，95%CI=2.07-22.2)。结论：组成性伽马-H_2AX和53BP1染色揭示了三重阴性乳腺肿瘤患者的亚群，其预后明显较差。(C)2011爱思唯尔爱尔兰有限公司。保留所有权利。放射治疗与肿瘤学101(2011)39-45
Background and purpose: Constitutive gamma-H2AX expression might indicate disruption of the DNA damage repair pathway, genomic instability, or shortened telomeric ends. Here, we quantified expression of endogenous gamma-H2AX and its downstream factor 53BP1 in a large number of breast cancer cell lines (n = 54) and a node-negative breast cancer cohort that had not received adjuvant systemic treatment (n = 122).Materials and methods: Formalin fixed paraffin embedded breast cancer cell lines and tumors were immunohistochemically analyzed for gamma-H2AX and 53BP1 expression, and related to cell line, patient and tumor characteristics and to disease progression.Results: In breast cancer cell lines, gamma-H2AX positivity was associated with the triple negative/basal like subgroup (p = 0.005), and with BRCA1 (p = 0.011) or p53 (p = 0.053) mutations. Specifically in triple negative breast cancer patients a high number of gamma-H2AX foci indicated a significantly worse prognosis (p = 0.006 for triple negative vs. p = 0.417 for estrogen receptor (ER), progesterone receptor (PR) or HER2 positive patients). A similar association with disease progression was found for 53BP1. In a multivariate analysis with tumor size, grade, and triple negativity, only the interaction between triple negativity and gamma-H2AX remained significant (p = 0.002, Hazard Ratio = 6.77, 95% CI = 2.07-22.2).Conclusions: Constitutive gamma-H2AX and 53BP1 staining reveals a subset of patients with triple negative breast tumors that have a significantly poorer prognosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 101 (2011) 39-45