Carcinogenesis Advance Access originally published online on August 19, 2004
Carcinogenesis 2004 25(12):2337-2343; doi:10.1093/carcin/bgh257
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Carcinogenesis vol.25 no.12 © Oxford University Press 2004; all rights reserved.
ARTICLE |
MRE11 expression is impaired in gastric cancer with microsatellite instability
1 Department of Experimental Medicine and Pathology, University ‘La Sapienza’, 00161 Rome, Italy, 2 Department of Oncology and Neurosciences, University ‘Gabriele D'Annunzio’ and Center for the Study on Aging (Ce.S.I.), G. D'Annunzio Foundation, 66013 Chieti, Italy, 3 Molecular and Nutritional Epidemiology Unit, CSPO, Scientific Institute of Tuscany, 50100 Florence, Italy and 4 Department of Pathology, University of Florence, 50100 Florence, Italy
5 To whom correspondence should be addressed Email: ottini{at}yahoo.com
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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