Journal Article

MRE11 expression is impaired in gastric cancer with microsatellite instability

Laura Ottini, Mario Falchetti, Calogero Saieva, Manola De Marco, Giovanna Masala, Ines Zanna, Milena Paglierani, Giuseppe Giannini, Alberto Gulino, Gabriella Nesi, Renato Mariani Costantini and Domenico Palli

in Carcinogenesis

Volume 25, issue 12, pages 2337-2343
Published in print December 2004 | ISSN: 0143-3334
Published online December 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh257
MRE11 expression is impaired in gastric cancer with microsatellite instability

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  • Clinical Cytogenetics and Molecular Genetics

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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.

Keywords: GC, gastric carcinoma; MMR, mismatch repair; MNR, hMRE11–NBS1–hRAD50 complex; MSI, microsatellite instability; MSI-H, high-level MSI; MSI-L, low-level MSI; MSS, MSI-negative

Journal Article.  5133 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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