Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype
Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype
复制标题
DOI：
10.1016/s0378-1119(01)00517-0
复制
发表时间：
2001-07-11
期刊：
影响因子：
3.5
通讯作者：
Perucho, M
中科院分区：
文献类型：
--
作者：
Ohmiya, N;Matsumoto, S;Perucho, M
遗传性和散发性胃肠道肿瘤的微卫星突变表型（MMP）的特点是显着的基因组不稳定性在简单的重复序列。基因组不稳定性通常由DNA错配修复（MMR）基因hMSH2和hMLH1的种系和体细胞突变引起。MMP也可以由hMLH1的表观遗传失活引起。MMP在含有单核苷酸重复序列的基因中产生许多体细胞移码突变。我们以前报道在MMP肿瘤中，hMSH6和hMSH3 MMR基因经常在其（C）（8）和（A）（8）轨道上携带移码突变。分别我们认为这些“继发性增变因子突变”有助于MMP的逐渐表现。在这里，我们报告的其他移码检测。胡说以及MMP的结肠癌和胃癌中这些基因的错义突变。一个生殖细胞移码突变被发现在hMSH6在结肠肿瘤窝藏另一个体细胞移码突变。在hMSH6中检测到几个种系序列变异和保守残基的体细胞错义突变，而在hMSH3中仅检测到一个。在3个hMSH6生殖系保守残基变异体中，1个与（C）（8）轨道的体细胞突变共存，另1个具有体细胞错义突变。我们认为，这些种系和体细胞的错义变异是致病的。虽然在一些肿瘤中发现了双等位基因hMSH6和hMSH3移码突变，但许多肿瘤似乎仅含有单等位基因突变。在一些肿瘤中，这些体细胞单等位基因移码突变在（C）（8）和（A），.，发现该轨迹与其他等位基因中的其他体细胞突变共存，支持它们在肿瘤发生期间的功能。然而，hMSH6和hMSH3中这些额外的体细胞突变的低发生率使得许多肿瘤仅具有单等位基因突变。通过比较分析不同基因型的不同肿瘤细胞克隆的RNA和蛋白质表达，研究移码突变对基因表达的影响。结果表明，hMSH6（C）（8）移码突变消除了蛋白质表达。排除了截短蛋白质的显性负效应。我们建议在累积单倍不足模型的背景下，这些二级单等位基因突变的功能。(C)2001爱思唯尔科技有限公司。保留所有权利。
Hereditary and sporadic gastrointestinal cancer of the microsatellite mutator phenotype (MMP) is characterized by a remarkable genomic instability at simple repeated sequences. The genomic instability is often caused by germline and somatic mutations in DNA mismatch repair (MMR) genes hMSH2 and hMLH1. The MMP can be also caused by epigenetic inactivation of hMLH1. The MMP generates many somatic frameshift mutations in genes containing mononucleotide repeats. We previously reported that in MMP tumors the hMSH6 and hMSH3 MMR genes often carry frameshift mutations in their (C)(8) and (A)(8) tracks. respectively. We proposed that these 'secondary mutator mutations' contribute to a gradual manifestation of the MMP. Here we report the detection of other frameshift. nonsense. and missense mutations in these genes in colon and gastric cancers of the MMP. A germline frameshift mutation was found in hMSH6 in a colon tumor harboring another somatic frameshift mutation. Several germline sequence variants and somatic missense mutations at conserved residues were detected in hMSH6 and only one was detected in hMSH3. Of the three hMSH6 germline variants in conserved residues, one coexisted with a somatic mutation at the (C)(8) track and another had a somatic missense mutation. We suggest that some of these germline and somatic missense variants are pathogenic. While biallelic hMSH6 and hMSH3 frameshift mutations were found in some tumors, many tumors seemed to contain only monoallelic mutations. In some tumors, these somatic monoallelic frameshift mutations at the (C)(8) and (A),., tracks were found to coexist with other somatic mutations in the other allele, supporting their functionality during tumorigenesis. However, the low incidence of these additional somatic mutations in hMSH6 and hMSH3 leaves many tumors with only monoallelic mutations. The impact of the frameshift mutations in gene expression was studied by comparative analysis of RNA and protein expression in different tumor cell clones with different genotypes. The results show that the hMSH6 (C)(8) frameshift mutation abolishes protein expression. ruling out a dominant negative effect by a truncated protein. We suggest the functionality of these secondary monoallelic mutator mutations in the context of an accumulative haploinsufficiency model. (C) 2001 Elsevier Science B.V. All rights reserved.