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.

MRE11 expression is impaired in gastric cancer with microsatellite instability / Ottini, Laura; M., Falchetti; C., Saieva; M., De Marco; G., Masala; I., Zanna; M., Paglierani; Giannini, Giuseppe; Gulino, Alberto; G., Nesi; R., Mariani Costantini; D., Palli. - In: CARCINOGENESIS. - ISSN 0143-3334. - STAMPA. - 25:12(2004), pp. 2337-2343. [10.1093/carcin/bgh257]

MRE11 expression is impaired in gastric cancer with microsatellite instability

OTTINI, LAURA;GIANNINI, Giuseppe;GULINO, Alberto;
2004

Abstract

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.
2004
01 Pubblicazione su rivista::01a Articolo in rivista
MRE11 expression is impaired in gastric cancer with microsatellite instability / Ottini, Laura; M., Falchetti; C., Saieva; M., De Marco; G., Masala; I., Zanna; M., Paglierani; Giannini, Giuseppe; Gulino, Alberto; G., Nesi; R., Mariani Costantini; D., Palli. - In: CARCINOGENESIS. - ISSN 0143-3334. - STAMPA. - 25:12(2004), pp. 2337-2343. [10.1093/carcin/bgh257]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/237582
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