Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis
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Author
Tricarico, Rossella
Cortellino, Salvatore
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
de Leon, Maurizio Ponz
Mancuso, Pietro
Devarajan, Karthik
Cai, Kathy Q.
Klein-Szanto, Andres J.P.
Neri, Giovanni
Møller, Pål
Viel, Alessandra
Genuardi, Maurizio
Fodde, Riccardo
Bellacosa, Alfonso
Note: Order does not necessarily reflect citation order of authors.
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Tricarico, R., S. Cortellino, A. Riccio, S. Jagmohan-Changur, H. van der Klift, J. Wijnen, D. Turner, et al. 2015. “Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis.” Oncotarget 6 (40): 42892-42904.Abstract
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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767479/pdf/Terms of Use
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