Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability
Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability
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DOI：
10.1038/sj.cdd.4401193
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发表时间：
2003-04-01
影响因子：
12.4
通讯作者：
Daniel, PT
中科院分区：
文献类型：
--
作者：
Mrózek, A;Petrowsky, H;Daniel, PT
胃癌对DNA损伤疗法是高度难治的。因此，我们研究了116例接受根治性R 0切除术的胃癌患者的p53和Bax基因突变和蛋白表达。Bax突变与严重的微卫星不稳定性（MSI）无关，即通过BAT-25/BAT-26微卫星标记分析确定的全局错配修复缺陷。因此，MSI移码突变是低MSI肿瘤的特征。相反，正如预期的那样，在微卫星不稳定肿瘤中没有观察到p53突变。p53突变或p53过表达对疾病预后无影响。然而，p53失活与β 2-突变肿瘤患者亚组的极差预后相关。因此，我们首次表明，线粒体凋亡途径的两个关键调节因子p53和Bax的联合突变导致了极其侵袭性的肿瘤生物学和不良的临床预后。
Gastric cancer is highly refractory to DNA-damaging therapies. We therefore studied both gene mutation and protein expression of p53 and Bax in a cohort of 116 patients with gastric cancer who underwent R0-resection with a curative intent. Bax mutation was independent from severe microsatellite instability (MSI), that is, global mismatch repair deficiency as determined by analysis of BAT-25/BAT-26 microsatellite markers. Thus, Bax-frameshift mutation is a feature of tumors with low MSI. In contrast and as expected, no p53 mutations were observed in the microsatellite instable tumors. p53 Mutation or p53 overexpression did not have an impact on disease prognosis. p53-Inactivation was, however, associated with an extremely poor prognosis in the subgroup of patients with Bax-mutated tumors. Thus, we show for the first time that the combined mutation of p53 and Bax, two key regulators of the mitochondrial apoptosis pathway, results in an extremely aggressive tumor biology and poor clinical prognosis.