Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis

Rossella Tricarico, Salvatore Cortellino, Antonio Riccio, Shantie Jagmohan-Changur, Heleen Van der Klift, Juul Wijnen, David Turner, Andrea Ventura, Valentina Rovella, Antonio Percesepe, Emanuela Lucci-Cordisco, Paolo Radice, Lucio Bertario, Monica Pedroni, Maurizio Ponz de Leon, Pietro Mancuso, Karthik Devarajan, Kathy Q. Cai, Andres J.P. Klein-Szanto, Giovanni NeriPål Møller, Alessandra Viel, Maurizio Genuardi, Riccardo Fodde, Alfonso Bellacosa

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish
Pages (from-to)42892-42904
Number of pages13
Issue number40
StatePublished - 2015


  • Animals
  • Carcinogenesis/genetics
  • Colorectal Neoplasms/genetics
  • DNA Mismatch Repair/genetics
  • DNA Mutational Analysis
  • Endodeoxyribonucleases/genetics
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Polymerase Chain Reaction


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