Prognostic Significance of Nuclear Phospho-ATM Expression in Melanoma.
Prognostic Significance of Nuclear Phospho-ATM Expression in Melanoma.
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DOI：
10.1371/journal.pone.0134678
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Rotte A
中科院分区：
文献类型：
--
作者：
Bhandaru M;Martinka M;McElwee KJ;Rotte A
紫外线辐射诱导的基因组不稳定性是黑色素瘤的主要原因之一。共济失调毛细血管扩张症突变（ATM）的磷酸化是DNA损伤后的初始事件之一。磷酸化ATM（p-ATM）在激活DNA修复和几种致癌途径以及维持基因组完整性中起关键作用。因此，本研究旨在了解p-ATM在黑色素瘤进展中的意义，并将其与患者预后相关。应用组织芯片和免疫组化技术研究p-ATM在黑色素瘤中的表达。共有366例黑色素瘤患者（230例原发性黑色素瘤和136例转移性黑色素瘤）用于本研究。采用卡方检验、Kaplan-Meier法、单因素及多因素考克斯回归分析等方法分析p-ATM表达与肺癌预后的关系。结果表明，无论是损失，并在增益，p-ATM表达与黑色素瘤的进展，从正常痣转移性黑色素瘤。与弱至中度表达的患者相比，样本显示阴性或强p-ATM染色的患者的5年生存率显著更差。p-ATM表达缺失与相对较好的5年生存率相关，但相应的10年生存率曲线几乎与p-ATM强表达的曲线重叠。发现p-ATM表达是5年而不是10年患者生存的独立预后因素。总之，我们的研究结果表明，p-ATM表达的丧失和p-ATM表达的获得是黑色素瘤患者生存率较差的指标。
UV radiation induced genomic instability is one of the leading causes for melanoma. Phosphorylation of Ataxia Telangiectasia Mutated (ATM) is one of the initial events that follow DNA damage. Phospho-ATM (p-ATM) plays a key role in the activation of DNA repair and several oncogenic pathways as well as in the maintenance of genomic integrity. The present study was therefore performed to understand the significance of p-ATM in melanoma progression and to correlate it with patient prognosis. Tissue microarray and immunohistochemical analysis were employed to study the expression of p-ATM in melanoma patients. A total of 366 melanoma patients (230 primary melanoma and 136 metastatic melanoma) were used for the study. Chi-square test, Kaplan-Meier, univariate and multivariate Cox regression analysis were used to elucidate the prognostic significance of p-ATM expression. Results revealed that both loss of, and gain in, p-ATM expression were associated with progression of melanoma from normal nevi to metastatic melanoma. Patients whose samples showed negative or strong p-ATM staining had significantly worse 5-year survival compared to patients who had weak to moderate expression. Loss of p-ATM expression was associated with relatively better 5-year survival, but the corresponding 10-year survival curve almost overlapped with that of strong p-ATM expression. p-ATM expression was found to be an independent prognostic factor for 5-year but not for 10-year patient survival. In conclusion our findings show that loss of p-ATM expression and gain-in p-ATM expression are indicators of worse melanoma patient survival.