Mutations of the 'minor' mismatch repair gene MSH6 in typical and atypical hereditary nonpolyposis colorectal cancer |
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Authors: | Emanuela Lucci-Cordisco Valentina Rovella Stefania Carrara Antonio Percesepe Monica Pedroni Alfonso Bellacosa Oana Caluseriu Mara Forasarig Marcello Anti Giovanni Neri Maurizio Ponz de Leon Alessandra Viel Maurizio Genuardi |
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Affiliation: | (1) Institutes of Medical Genetics, 'A.Gemelli' School of Medicine, Catholic University, Rome, Italy;(2) Institutes of Internal Medicine and Geriatrics, 'A.Gemelli' School of Medicine, Catholic University, Rome, Italy;(3) Institutes of Medical Genetics, 'A.Gemelli' School of Medicine, Catholic University, Largo Francesco Vito 1, 00168 Rome, Italy;(4) Department of Internal Medicine, University of Modena and Reggio Emilia, Policlinico, Modena, Italy;(5) Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, USA;(6) Division of Gastroenterology, Centro di Riferimento Oncologico-IRCCS, Via Pedemontana Occidentale 12, 33081 Aviano (PN), Italy;(7) Divisions of Experimental Oncology 1, Centro di Riferimento Oncologico-IRCCS, Aviano (PN), Italy;(8) Medical Genetics, Department of Clinical Physiopathology, University of Florence, Florence, Italy |
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Abstract: | Mutations of the mismatch repair (MMR) genes MLH1 and MSH2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant autosomal dominant condition characterized by hypermutability of short tandemly repeated sequences in tumor DNA. Mutations of another MMR gene, MSH6, seem to be less common than MLH1 and MSH2 defects, and have been mostly observed in atypical HNPCC families, characterized by a weaker tumor family history, higher age at disease onset, and low degrees of microsatellite instability (MSI), predominantly involving mononucleotide runs. We have investigated the MSH6 gene sequence in the peripheral blood of 4 HNPCC and 20 atypical HNPCC probands. Two frameshift mutations within exon 4 were detected in 2 patients. One mutation was found in a proband from a typical HNPCC family, who had developed a colorectal cancer (CRC), a gastric cancer and a rectal adenoma. The CRC and the adenoma showed mild MSI limited to mononucleotide tracts, while the gastric carcinoma was microsatellite stable. The other mutation was detected in an atypical HNPCC proband, whose CRC showed widespread MSI involving both mono- and dinucleotide repeats. The phenotypic variability associated with MSH6 constitutional mutations represents a complicating factor for the optimization of strategies aimed at identifying candidates to MSH6 genetic testing. |
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Keywords: | colorectal cancer DNA mismatch repair familial cancer hereditary cancer Mmicrosatellite instability |
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