TY - JOUR
T1 - Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis
AU - Tricarico, Rossella
AU - Cortellino, Salvatore
AU - Riccio, Antonio
AU - Jagmohan-Changur, Shantie
AU - Van der Klift, Heleen
AU - Wijnen, Juul
AU - Turner, David
AU - Ventura, Andrea
AU - Rovella, Valentina
AU - Percesepe, Antonio
AU - Lucci-Cordisco, Emanuela
AU - Radice, Paolo
AU - Bertario, Lucio
AU - Pedroni, Monica
AU - de Leon, Maurizio Ponz
AU - Mancuso, Pietro
AU - Devarajan, Karthik
AU - Cai, Kathy Q.
AU - Klein-Szanto, Andres J.P.
AU - Neri, Giovanni
AU - Møller, Pål
AU - Viel, Alessandra
AU - Genuardi, Maurizio
AU - Fodde, Riccardo
AU - Bellacosa, Alfonso
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Animals
KW - Carcinogenesis/genetics
KW - Colorectal Neoplasms/genetics
KW - DNA Mismatch Repair/genetics
KW - DNA Mutational Analysis
KW - Endodeoxyribonucleases/genetics
KW - Female
KW - Humans
KW - Male
KW - Mice
KW - Mice, Knockout
KW - Mutation
KW - Oligonucleotide Array Sequence Analysis
KW - Phenotype
KW - Polymerase Chain Reaction
UR - http://www.scopus.com/inward/record.url?scp=84952359728&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.5740
DO - 10.18632/oncotarget.5740
M3 - Article
C2 - 26503472
AN - SCOPUS:84952359728
SN - 1949-2553
VL - 6
SP - 42892
EP - 42904
JO - Oncotarget
JF - Oncotarget
IS - 40
ER -
