title: A rare MSH2 mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage.
abstract: Lynch syndrome is caused by germline mutations in 1 of the 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). Mutations in MSH2 cause concomitant loss of hMSH6, whereas MLH1 mutations lead to concurrent loss of PMS2. Much less frequent mutations in MSH6 or PMS2 are associated with the isolated loss of the corresponding proteins. We here demonstrate the causative role of the first germline mutation of MSH2, c.1249-1251 dupGTT (p.417V-418I dupV), associated with normal hMSH2 expression and lack of hMSH6 protein despite a normal MSH6 gene sequence. hMSH6 protein was completely lost only in advanced cancer stages due to 2 different "second hits": a whole MSH2 gene deletion and a frame-shifting insertion in the MSH6 (C)8 repeat in the coding sequence.
authors.affiliation: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, Università di Bari "Aldo Moro", 70124 Bari, Italy.
authors.forename: Daria Carmela
authors.initials: DC
authors.lastname: Loconte
authors.affiliation: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, Università di Bari "Aldo Moro", 70124 Bari, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Patruno
authors.affiliation: Geriatric Unit and Rare Disease Center, University Hospital of Bari, 70124 Bari, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lastella
authors.affiliation: Department of Laboratory, Pathology, and Legal Medicine, University Hospital Polyclinic of Modena, 41124 Modena, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Di Gregorio
authors.affiliation: National Cancer Institute, IRCCS Oncologico Giovanni Paolo II, 70124 Bari, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Grossi
authors.affiliation: Cancer Genetics Laboratory, IRCCS "De Bellis", 70013 Castellana Grotte BA, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Forte
authors.affiliation: Department of Emergency and Organ Transplant, Universita' di Bari "Aldo Moro", 70124 Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ingravallo
authors.affiliation: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, Università di Bari "Aldo Moro", 70124 Bari, Italy.
authors.forename: Dora
authors.initials: D
authors.lastname: Varvara
authors.affiliation: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, Università di Bari "Aldo Moro", 70124 Bari, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Bagnulo
authors.affiliation: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, Università di Bari "Aldo Moro", 70124 Bari, Italy; National Cancer Institute, IRCCS Oncologico Giovanni Paolo II, 70124 Bari, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
authors.affiliation: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, Università di Bari "Aldo Moro", 70124 Bari, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.affiliation: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, Università di Bari "Aldo Moro", 70124 Bari, Italy. Electronic address: alessandro.stella@uniba.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stella
mesh_terms: D000328:Adult; D001483:Base Sequence; D015153:Blotting, Western; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011485:Protein Binding
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: Lynch syndrome; MSH2; MSH6; Mismatch repair; Second hit; Variants of unknown significance