Assessing the pathogenicity of MLH1 missense mutations in patients with suspected hereditary nonpolyposis colorectal cancer:: correlation with clinical, genetic and functional features
Assessing the pathogenicity of MLH1 missense mutations in patients with suspected hereditary nonpolyposis colorectal cancer:: correlation with clinical, genetic and functional features
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DOI：
10.1038/sj.ejhg.5201628
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发表时间：
2006-07-01
影响因子：
5.2
通讯作者：
Porfiri, Emilio
中科院分区：
文献类型：
--
作者：
Belvederesi, Laura;Bianchi, Francesca;Porfiri, Emilio
评估MLH1和MSH2错义突变的致病性对于为疑似遗传性非息肉病性结直肠癌(HNPCC)患者提供咨询至关重要。大约32%的MLH1突变和18%的MSH2突变是错义突变，通常具有不确定的遗传意义。为了研究在5例疑似HNPCC、P648S(CCC-TCC)、L559R(CTG-CGG)、K618A(AAG-GCG)、Y646C(TAT-TGT)患者中发现的4个MLH1错义突变的致病性，我们研究了它们破坏MLH1蛋白功能的能力及其与典型的临床、遗传和病理特征的关系。我们的结果表明，P648S和L559R突变可能是致病的，因为它们在体外干扰了MLH1蛋白与其伴侣PMS2的相互作用，并取消了HCT116细胞中MLH1的表达。此外，这些变异与HNPCC患者中常见的特征有关：特别是高微卫星不稳定性，高级别肿瘤的发生，以及在一例中，强烈的家族史。K618A和Y646C突变的致病性值得怀疑，因为它们与HNPCC典型特征的相关性较低，功能分析的结果也不明确。这些观察结果表明，通过分析蛋白质功能丧失、微卫星不稳定的发生和家族史等多重突变特征，可以在临床上评估MLH错义突变的致病性。
Assessing the pathogenicity of missense mutations of MLH1 and MSH2 is critical to counsel patients with suspected hereditary nonpolyposis colorectal cancer (HNPCC). Approximately 32% of all MLH1 mutations and 18% of MSH2 mutations are missense variants which often have an uncertain genetic significance. To assess the pathogenicity of four MLH1 missense mutations which were found in five patients with suspected HNPCC, P648S (CCC-TCC), L559R (CTG-CGG), K618A (AAG-GCG), Y646C (TAT-TGT), we studied their ability to disrupt MLH1 protein function and their relationship with all those clinical, genetic and pathological features which are typical of this syndrome. Our results indicated that the P648S and L559R mutations were probably pathogenic because they disrupted MLH1 protein interaction with its partner PMS2 in vitro and abolished MLH1 expression in HCT116 cells. In addition these variants were associated with features often found in HNPCC patients: in particular high microsatellite instability, occurrence of high grade tumours and, in one case, strong family history. The pathogenicity of the K618A and Y646C mutations was questionable as their correlation with features typical of HNPCC was low and the outcome of the functional analysis was ambiguous. These observations suggested that a clinically usable assessment of the pathogenicity of MLH missense variants can be achieved through the analysis of multiple mutation characteristics among which loss of protein function, occurrence of microsatellite instability and family history seemed to have a predominant role.