Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer
Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer
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DOI：
10.1158/1078-0432.ccr-05-2105
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发表时间：
2006-03-01
影响因子：
11.5
通讯作者：
Mueller, W
中科院分区：
文献类型：
--
作者：
Grabsch, H;Dattani, M;Mueller, W
目的：双链断裂 (DSB) 是导致染色体畸变的主要 DNA 损伤，忠实修复对于维持基因组稳定性至关重要。关于 DNA DSB 修复蛋白在结直肠癌中的表达知之甚少。为了解决这个问题，我们检查了 DSB 修复关键蛋白 ATM、BRCA1、BRCA2、Ku70 和 Ku80 的表达模式，以及它们在大量结直肠癌患者生存中的假定作用。 实验设计：通过使用针对所研究的各种蛋白质的特异性抗体，对 342 例散发性结直肠癌进行免疫组织化学分析。将染色结果与临床病理数据、患者生存率以及错配修复蛋白 MLH1 和 MSH2 的表达进行比较。结果：ATM 和 BRCA1 的表达模式预测所有结直肠癌患者以及接受辅助治疗的一小部分患者的生存率。 ATM 和 BRCA1 的低表达与 MLH1 或 MSH2 表达缺失相关。结论：这是第一项显示 DNA DSB 修复蛋白 ATM 和 BRCA1 的表达与结直肠癌患者生存之间关系的研究。现在有必要对大型随机试验进行肿瘤研究，以验证我们的试点数据并确定免疫组织化学测定在预测对特定辅助治疗方案的反应方面的临床有效性。此外，我们的结果表明散发性结直肠癌中 DNA 错配修复的表达与 DNA DSB 修复蛋白之间可能存在联系，值得进一步研究。
Purpose: The double-strand break (DSB) is the major DNA lesion leading to chromosomal aberrations and faithful repair is crucial for maintaining genomic instability. Very little is known about the expression of DNA DSB repair proteins in colorectal cancer. To address this issue, we examined the expression pattern of DSB repair key proteins ATM, BRCA1, BRCA2, Ku70, and Ku80 and their putative role in patients survival in a large series of colorectal cancer.Experimental Design: 342 sporadic colorectal cancer were subjected to immunohistochemistry by using specific antibodies for the various proteins investigated. Staining results were compared with clinicopathologic data, patient survival, as well as expression of mismatch repair proteins MLH1 and MSH2.Results: The expression pattern of both ATM and BRCA1 predicted survival in all colorectal cancer patients as well as in the small subgroup of patients that received adjuvant therapy. Low expression of ATM and BRCA1 was associated with loss of MLH1 or MSH2 expression.Conclusions: This is the first study to show a relationship between the expression of DNA DSB repair proteins ATM and BRCA1 and survival in colorectal cancer patients. Studies in tumors from large randomized trials are now necessary to validate our pilot data and establish the clinical usefulness of the immunohistochemical assay in predicting response to a particular adjuvant therapy regimen. Furthermore, our results indicate a possible link between expression of DNA mismatch repair and DNA DSB repair proteins in sporadic colorectal cancer, which warrants further investigation.