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Tricarico R , Cortellino S , Riccio A , Jagmohan-Changur S , Van der Klift H , Wijnen J , Turner D , Ventura A , Rovella V , Percesepe A , Lucci-Cordisco E , Radice P , Bertario L , Pedroni M , Ponz de Leon M , Mancuso P , Devarajan K , Cai KQ , Klein-Szanto AJ , Neri G , Moller P , Viel A , Genuardi M , Fodde R , Bellacosa A
Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis
Oncotarget. 2015 Oct 16;6(40) :42892-904
PMID: 26503472    PMCID: PMC4767479    URL: http://www.ncbi.nlm.nih.gov/pubmed/26503472
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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.
Tricarico, Rossella Cortellino, Salvatore Riccio, Antonio Jagmohan-Changur, Shantie Van der Klift, Heleen Wijnen, Juul Turner, David Ventura, Andrea Rovella, Valentina Percesepe, Antonio Lucci-Cordisco, Emanuela Radice, Paolo Bertario, Lucio Pedroni, Monica Ponz de Leon, Maurizio Mancuso, Pietro Devarajan, Karthik Cai, Kathy Q Klein-Szanto, Andres J P Neri, Giovanni Moller, Pal Viel, Alessandra Genuardi, Maurizio Fodde, Riccardo Bellacosa, Alfonso Oncotarget. 2015 Oct 16. doi: 10.18632/oncotarget.5740.