Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade
Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade
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DOI：
10.1038/sj.bjc.6601804
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发表时间：
2004-05-17
影响因子：
8.8
通讯作者：
Shen, CY
中科院分区：
文献类型：
--
作者：
Ding, SL;Sheu, LF;Shen, CY
DNA 双链断裂 (DSB) 检查点/修复基因 ATM、BRCA1 和 TP53 在散发性乳腺癌中的作用需要澄清，因为 ATM 和 BRCA1 突变在散发性肿瘤中很少见。为了解释这一现象，我们假设（i）除了基因缺失之外，DSB检查点/修复蛋白的异常表达可能会废除这些基因的功能；（ii）在乳腺癌发病机制中可能存在单个缺陷基因的综合效应。使用 74 个早发（小于或等于 35 岁）浸润性导管癌标本组成的基本同质组，我们检查了病理分级与 ATM、BRCA1 和 TP53 基因缺失和/或异常蛋白表达之间的关联。结果表明，高级别肿瘤表现出 ATM、BRCA1 和 TP53 杂合性丢失 (LOH) 频率高和/或异常表达。多基因分析显示 BRCA1 异常与高级别肿瘤独立相关。 ATM和TP53似乎发挥了辅助作用，这些基因的异常显着增加了BRCA1异常的肿瘤分化不良的可能性。此外，这三个基因中较多的异常（LOH 或异常表达）与肿瘤分化不良相关。因此，这项研究表明，属于共同功能途径的几个 DSB 检查点/修复基因的组合变化与乳腺癌发病机制相关。 (C) 2004 年英国癌症研究中心。
The role of the DNA double-strand-break (DSB) checkpoint/repair genes, ATM, BRCA1 and TP53, in sporadic breast cancer requires clarification, since ATM and BRCA1 mutations are rare in sporadic tumours. In an attempt to explain this phenomenon, we postulated that (i) in addition to genetic deletion, abnormal expression of DSB checkpoint/repair proteins might abolish the function of these genes and (ii) there might be a combined effect of individual defective genes during breast cancer pathogenesis. Using a largely homogenous group of 74 specimens of early-onset (less than or equal to35 years of age) infiltrating ductal carcinomas, we examined associations between pathological grade and genetic deletion and/or abnormal protein expression of ATM, BRCA1 and TP53. The results showed that high-grade tumours displayed a high frequency of loss of heterozygosity (LOH) at, and/or abnormal expression of, ATM, BRCA1 and TP53. Multigenetic analysis showed abnormalities in BRCA1 to be independently associated with high-grade tumours. ATM and TP53 appeared to play an assistant role, abnormalities in these genes significantly increasing the possibility of poor differentiation in tumours with abnormalities in BRCA1. Furthermore, a higher number of abnormalities (LOH or abnormal expression) in these three genes correlated with poor tumour differentiation. Thus, this study suggests that combined changes in several DSB checkpoint/repair genes belonging to a common functional pathway are associated with breast cancer pathogenesis. (C) 2004 Cancer Research UK.