Carcinogenesis Advance Access published online on August 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh257
© 2004 by Oxford University Press
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1 Department of Experimental Medicine and Pathology, University "La Sapienza", 00161 Rome, Italy
* To whom correspondence should be addressed. E-mail: 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 analyzed the poly(T)11 tract constituting an accessory splicing signal within the intron 4 of 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 bp and 1bp at the MRE11poly(T)11 were identified in 33% and 48% MSI-H GCs, respectively. Biallelic mutations were frequently observed (77%) in GCs harbouring 2bp deletions. The presence of MRE11poly(T)11 2bp deletion was associated with a totally absent or strongly reduced MRE11 immunostaining (P<0.001) and with positive GC family history (P=0.046). Immunoblotting assays confirmed the absence of MRE11 expression in GCs with 2bp deletion. The relatively high frequency of 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.
Revised July 17, 2004
Accepted August 2, 2004
CANCER BIOLOGY
MRE11 expression is impaired in gastric cancer with microsatellite instability
2 Department of Experimental Medicine and Pathology, University "La Sapienza", 00161 Rome, Italy; Department of Oncology and Neurosciences, University "Gabriele D'Annunzio", 66013 Chieti, Italy; 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
4 Department of Pathology, University of Florence, 50100 Florence, Italy
5 Department of Oncology and Neurosciences, University "Gabriele D'Annunzio", 66013 Chieti, Italy; Center for the Study on Aging (Ce.S.I.), G. D'Annunzio Foundation, 66013 Chieti, Italy
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