Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis
Autor: | Andrea Ventura, Riccardo Fodde, Antonio Percesepe, Alfonso Bellacosa, David P. Turner, Valentina Rovella, Maurizio Ponz de Leon, Karthik Devarajan, Juul T. Wijnen, Maurizio Genuardi, Pietro Mancuso, Salvatore Cortellino, Andres J. Klein-Szanto, Emanuela Lucci-Cordisco, Antonio Riccio, Rossella Tricarico, Heleen M. van der Klift, Pål Møller, Alessandra Viel, Kathy Q. Cai, Monica Pedroni, Paolo Radice, Lucio Bertario, Shantie Jagmohan-Changur, Giovanni Neri |
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Přispěvatelé: | Pathology, Neurology |
Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Male
Carcinogenesis Knockout DNA Mutational Analysis HNPCC MBD4/MED1 colorectal cancer mismatch repair mutations Settore MED/09 Settore MED/03 - GENETICA MEDICA medicine.disease_cause DNA Mismatch Repair Polymerase Chain Reaction Settore MED/06 MBD4 03 medical and health sciences Mice 0302 clinical medicine Genotype Medicine Missense mutation Animals Humans 030304 developmental biology Oligonucleotide Array Sequence Analysis Genetics Mice Knockout 0303 health sciences Mutation Endodeoxyribonucleases business.industry Phenotype digestive system diseases 3. Good health Settore MED/03 Oncology CpG site 030220 oncology & carcinogenesis DNA mismatch repair Female business Colorectal Neoplasms Research Paper |
Zdroj: | Oncotarget Oncotarget, 6(40), 42892-42904. Impact Journals LLC |
ISSN: | 1949-2553 |
Popis: | The DNA glycosylase gene MBD4 safeguards genomic stability at CpG sites and is frequently mutated at coding poly-A tracks in mismatch repair (MMR)-defective colorectal tumors (CRC). Mbd4 biallelic inactivation in mice provided conflicting results as to its role in tumorigenesis. Thus, it is unclear whether MBD4 alterations are only secondary to MMR defects without functional consequences or can contribute to the mutator phenotype. We investigated MBD4 variants in a large series of hereditary/familial and sporadic CRC cases. Whereas MBD4 frameshifts were only detected in tumors, missense variants were found in both normal and tumor DNA. In CRC with double-MBD4/MMR and single-MBD4 variants, transition mutation frequency was increased, indicating that MBD4 defects may affect the mutational landscape independently of MMR defect. Mbd4-deficient mice showed reduced survival when combined with Mlh1-/- genotype. Taken together, these data suggest that MBD4 inactivation may contribute to tumorigenesis, acting as a modifier of MMR-deficient cancer phenotype. |
Databáze: | OpenAIRE |
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