Microsatellite gene instability and abnormality of mismatch gene proteins in human lung cancer from chromate-exposed workers

我们之前对铬酸盐暴露工人的肺癌研究表明，铬酸盐暴露会诱发人类肺癌p53基因的特定突变模式（Biochem Biophys Res Com 139,95 - 100,1997）。在这项研究中，我们使用6个微卫星标记检测了来自33名铬酸盐暴露工人和29名非铬酸盐暴露肺癌患者（对照样本）的40例肺癌的基因组不稳定性。40例铬酸盐暴露肿瘤中有30例（75.0%）表现为RER+。另一方面，没有铬酸盐暴露的29个肿瘤中只有4个（13.3%）表现出复制错误阳性表型（RER+）。铬酸盐暴露肿瘤中RER+的频率高于未铬酸盐暴露肿瘤（p<0.0001）。此外，铬酸盐暴露时间与MSI阳性数有关，而与Brinkman指数无关。为了阐明RER+与错配修复基因异常的关系，我们采用免疫组化方法检测了28例铬酸盐肺癌和28例非铬酸盐肺癌中hMLH1和hMSH2蛋白的表达。所有28例非铬酸盐肺癌均强烈表达hMLH1和hMSH蛋白。另一方面，28例铬酸盐肺癌中有14例（50%）中度或弱表达hMLH蛋白。28例铬酸盐肺癌中有8例（29%）中度或弱表达hMSH蛋白。铬酸盐肺癌中RER+可能与错配修复基因异常有关。

Our previous study for human lung cancer from chromate-exposure workers have revealed that chromate exposure induce the particular mutation pattern in the p53 gene of human lung cancer (Biochem Biophys Res Com 139, 95-100, 1997). In this study, we examined the genomic instability in 40 Lung cancers from 33 chromate-exposure workers and 29 lung cancers patients without chromate exposure (control samples) using 6 microsatellite markers. Thirty (75.0%) of the 40 tumors with chromate exposure showed RER+. On the other hand, only 4 (13.3%) of the 29 tumors without chromate exposure showed the replication error-positive phenotype (RER+). The frequency of RER+ in tumors with chromate exposure was higher than that in tumors without chromate exposure (p<0.0001). Moreover, the duration of chromate exposure but not Brinkman index may be associated with numbers of MSI positive.To clarify the relationship between RER+ and the abnormality of mismatch repair gene, we examined the expressions of hMLH1 and hMSH2 protein in 28 chromate lung cancers and 28 non-chromate lung cancers by immunohistochemistry. All 28 non-chromate lung cancers strongly expressed both hMLH1 and hMSH proteins. On the other hand, 14 (50%) of 28 chromate lung cancers moderately or weakly expressed hMLH protein. Eight (29%) of 28 chromate lung cancers moderately or weakly expressed hMSH protein. It is possible that RER+ in chromate lung cancer may be due to the abnormality of mismatch repair genes.