MRE11 expression is impaired in gastric cancer with microsatellite instability
MRE11 expression is impaired in gastric cancer with microsatellite instability
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DOI：
10.1093/carcin/bgh257
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发表时间：
2004-12-01
期刊：
影响因子：
4.7
通讯作者：
Palli, D
中科院分区：
文献类型：
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作者：
Ottini, L;Falchetti, M;Palli, D
具有高水平微卫星不稳定性（MSI-H）的胃癌（GC）的特征是编码和非编码单核苷酸重复序列的广泛突变。预测编码单核苷酸序列的缺失会引起移码突变并改变正常蛋白质功能。影响非编码单核苷酸重复序列的突变，如果发生在基因调控区，可能会导致功能性后果。为了研究癌症相关基因内的非编码多聚嘧啶段的突变是否可能导致MSI-H GC的表型，我们分析了MRE 11基因内含子4内构成辅助剪接信号的poly（T）11段。通过基于PCR的试验，在来自意大利中部托斯卡纳高风险地区鉴定的一系列充分表征的GC的27个MSI-H、22个MSI-低和29个MSI-阴性GC中评价了内含子MRE 11 poly（T）11的突变。在33和48%的MSI-H GC中分别鉴定出MRE 11 poly（T）11处2和1 bp的缺失。双等位基因突变经常观察到（77%）在GC窝藏2 bp缺失。MRE 11 poly（T）11 2 bp缺失与MRE 11免疫染色完全缺失或显著降低（P < 0.001）和阳性GC家族史相关（P = 0.046）。免疫印迹分析证实了在GC中缺失2 bp的MRE 11表达的缺失。MRE 11 poly（T）11突变的相对高频率、双等位基因突变的发生和蛋白表达缺失的证据表明MRE 11是MSI-H GC中的新突变靶点。总体而言，我们的研究结果表明，MSI相关的突变发生在非编码重复序列可能会影响蛋白质表达的MSI-H GC。
Gastric carcinomas (GCs) with high-level microsatellite instability (MSI-H) are characterized by widespread mutations at coding and non-coding mononucleotide repeats. Deletions at coding mononucleotide tracts are predicted to cause frameshift mutations and alter normal protein functions. Mutations affecting non-coding mononucleotide repeats may lead to functional consequences if they occur in gene regulatory regions. To investigate whether mutations in non-coding polypyrimidine tracts within cancer-related genes may contribute to the phenotype of MSI-H GCs, we analysed the poly(T)11 tract constituting an accessory splicing signal within the intron 4 of the MRE11 gene. Mutations at the intronic MRE11 poly(T)11 were evaluated by PCR-based assay in 27 MSI-H, 22 MSI-low and 29 MSI-negative GCs derived from a well-characterized series of GCs identified in a high-risk area in Tuscany, Central Italy. Deletion of 2 and 1 bp at the MRE11poly(T)11 were identified in 33 and 48% MSI-H GCs, respectively. Biallelic mutations were frequently observed (77%) in GCs harbouring 2 bp deletions. The presence of MRE11poly(T)11 2 bp deletion was associated with a totally absent or strongly reduced MRE11 immunostaining (P < 0.001) and with a positive GC family history (P = 0.046). Immunoblotting assays confirmed the absence of MRE11 expression in GCs with a 2 bp deletion. The relatively high frequency of the MRE11poly(T)11 mutations, the occurrence of biallelic mutations and the evidence of loss of protein expression indicate MRE11 as novel mutational target in MSI-H GC. Overall, our results indicate that MSI-associated mutations occurring in non-coding repeats may affect protein expression in MSI-H GC.