MRE11 expression is impaired in gastric cancer with microsatellite instability

被引:46
|
作者
Ottini, L [1 ]
Falchetti, M
Saieva, C
De Marco, M
Masala, G
Zanna, I
Paglierani, M
Giannini, G
Gulino, A
Nesi, G
Costantini, RM
Palli, D
机构
[1] Univ Roma La Sapienza, Dept Expt Med & Pathol, I-00161 Rome, Italy
[2] G DAnnunzio Fdn, Ctr Study Aging CeSI, I-66013 Chieti, Italy
[3] Univ Gabriele DAnnunzio, Dept Oncol & Neurosci, I-66013 Chieti, Italy
[4] Sci Inst Tuscany, Mol & Nutr Epidemiol Unit, CSPO, I-50100 Florence, Italy
[5] Univ Florence, Dept Pathol, I-50100 Florence, Italy
关键词
D O I
10.1093/carcin/bgh257
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页码:2337 / 2343
页数:7
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