Pathogenicity of the hereditary colorectal cancer mutation hMLH1 del616 linked to shortage of the functional protein
Pathogenicity of the hereditary colorectal cancer mutation hMLH1 del616 linked to shortage of the functional protein
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DOI：
10.1016/s0016-5085(03)00905-3
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发表时间：
2003-08-01
期刊：
影响因子：
29.4
通讯作者：
Nyström-Lahti, M
中科院分区：
文献类型：
--
作者：
Raevaara, TE;Vaccaro, C;Nyström-Lahti, M
背景与目的：遗传性非息肉病性结直肠癌与错配修复缺陷有关。大多数易感突变会阻止功能错配修复蛋白的产生。因此，当野生型复制也被灭活时，细胞变得错配修复缺陷，这导致肿瘤中高度的微卫星不稳定性。然而，与非截断突变相关的肿瘤可能表现出突变蛋白的免疫组织化学阳性或部分阳性，以及低或不典型的微卫星不稳定状态，这表明功能活性受损，但并不完全缺乏错配修复。我们发现人类突变L同源(HMLH)1 del616是遗传性非息肉病性结直肠癌中最普遍的复发突变之一，存在于一个大型遗传性非息肉病性结直肠癌家族中。由于预测的编码变化仅为1个氨基酸的缺失，因此对该突变的致病性进行了评估。方法：通过多种方法检测hMLH1del616的致病性，并研究突变的信使RNA和蛋白的表达和功能。结果：遗传和免疫组织化学证据支持该家族中hMLH1相关的癌症易感性。微卫星不稳定性由低到高不等，2例肿瘤中hMLH1蛋白缺失，1例肿瘤中可部分检测到hMLH1蛋白。而在体外错配修复实验中，突变的hMLH1 del616蛋白和野生型hMLH：1蛋白的功能相同，而体内表达的hMLH1 del616蛋白的量远远低于野生型蛋白的量，这表明缺失给突变蛋白带来了不稳定性。结论：我们的结果提示hMLH1 del616的致病性不是与无功能有关，而是与功能蛋白的缺乏有关。
Background & Aims: Hereditary nonpolyposis colorectal cancer is associated with mismatch repair deficiency. Most predisposing mutations prevent the production of functional mismatch repair protein. Thus, when the wildtype copy is also inactivated, the cell becomes mismatch repair deficient, and this leads to a high degree of microsatellite instability in tumors. However, tumors linked to nontruncating mutations may display positive or partly positive immunohistochemical staining of the mutated protein and low or atypical microsatellite instability status, which suggests impaired functional activity but not a total lack of mismatch repair. We found human mutL homology (hMLH) 1 del616, one of the most widespread recurring mutations in hereditary nonpolyposis colorectal cancer, segregating in a large hereditary nonpolyposis colorectal cancer family. Because the predicted coding change is a deletion of only :1 amino acid, the pathogenicity of the mutation was evaluated. Methods: Many analyses were performed to assess the pathogenicity of hMLH1 del616 and to study the expression and function of the mutated messenger RNA and protein. Results: Genetic and immunohistochemical evidence supported hMLH1-linked cancer predisposition in this family. Microsatellite instability varied from low to high, and the hMLH1 protein was lost in 2 tumors but was partly detectable in :1 tumor. Whereas similar optimal amounts of mutated hMLH1 del616 and wild-type hMLH:1 proteins were equally functional in an in vitro mismatch repair assay, the amount of in vivo-expressed hMLH1 del616 was much lower than the amount of wild-type protein; this suggests that the deletion imparts instability to the mutant protein. Conclusions: Our results suggest that the pathogenicity of hMLH1 del616 is not linked to nonfunctionality, but to shortage of the functional protein.