title: Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability.
abstract: Frequent mutations of coding nucleotide repeats are thought to contribute significantly to carcinogenesis associated with microsatellite instability (MSI). We have shown that shortening of the poly(T)11 within the polypyrimidine stretch/accessory splicing signal of human MRE11 leads to the reduced expression and functional impairment of the MRE11/NBS1/RAD50 complex. This mutation was selectively found in mismatch repair (MMR) defective cell lines and potentially identifies MRE11 as a novel target for MSI. Here, we examined 70 microsatellite unstable primary human cancers and we report that MRE11 mutations occur in 83.7 and 50% of the colorectal and endometrial cancers, respectively. In the colorectal cancer series, mutated MRE11 is more frequently associated with advanced age at diagnosis and A/B stages. Biallelic mutations were present in 38.8% of the cases and more frequently associated with lower (G1/G2) grade tumors. Impaired MRE11 expression was prevalent in primary colorectal tumors with larger and biallelic shortening of the poly(T)11. Immunohistochemistry confirmed the impaired MRE11 expression and revealed NBS1-defective expression in MRE11 mutated cancers. Together with the observation that perturbation of the MRE11/NBS1/RAD50 complex predisposes to cancer, our work highlights MRE11 as a new common target in the MMR deficient tumorigenesis and suggests its role in colorectal carcinogenesis.
authors.affiliation: Department of Experimental Medicine and Pathology, University La Sapienza, Policlinico Umberto I, Viale Regina Elena, 324, 00161 Rome, Italy. guiseppe.giannini@uniroma1.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Christian
authors.initials: C
authors.lastname: Rinaldi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ristori
authors.forename: Maria Irene
authors.initials: MI
authors.lastname: Ambrosini
authors.forename: Fabio
authors.initials: F
authors.lastname: Cerignoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.forename: Ettore
authors.initials: E
authors.lastname: Bidoli
authors.forename: Silvia
authors.initials: S
authors.lastname: Berni
authors.forename: Giulia
authors.initials: G
authors.lastname: D'Amati
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
mesh_terms: D000368:Aged; D000483:Alleles; D020137:Base Pair Mismatch; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D043243:DNA Sequence, Unstable; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000096:biosynthesis* / Q000235:genetics*; D005090:Exodeoxyribonucleases / Q000096:biosynthesis* / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; C086930:RAD50 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C094191:MRE11 protein, S cerevisiae