Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis.
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.
Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
Rossella
R
Tricarico
IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
Salvatore
S
Cortellino
Department of Cardiology, Boston Children's Hospital, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, United States of America.
Antonio
A
Riccio
Department of Pathology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
Shantie
S
Jagmohan-Changur
Department of Clinical Genetics and Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Heleen
H
Van der Klift
Department of Clinical Genetics and Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Juul
J
Wijnen
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
David
D
Turner
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York City, New York, United States of America.
Andrea
A
Ventura
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Valentina
V
Rovella
Medical Genetics Unit, Department of Mother & Child, University Hospital of Modena, Modena, Italy.
Antonio
A
Percesepe
Institute of Medical Genetics, Catholic University of the Sacred Heart, "A. Gemelli" School of Medicine, Rome, Italy.
Emanuela
E
Lucci-Cordisco
Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Paolo
P
Radice
Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Lucio
L
Bertario
Department of Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.
Monica
M
Pedroni
Department of Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.
Maurizio
M
Ponz de Leon
Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.|Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
Pietro
P
Mancuso
Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
Karthik
K
Devarajan
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
Kathy Q
KQ
Cai
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
Andres J P
AJ
Klein-Szanto
Institute of Medical Genetics, Catholic University of the Sacred Heart, "A. Gemelli" School of Medicine, Rome, Italy.
Giovanni
G
Neri
Inherited Cancer Research Group, Department for Medical Genetics, The Norwegian Radium Hospital, University Hospital, Oslo, Norway.
Pål
P
Møller
Experimental Oncology 1, CRO Aviano, National Cancer Institute, Aviano (PN), Italy.
Alessandra
A
Viel
Institute of Medical Genetics, Catholic University of the Sacred Heart, "A. Gemelli" School of Medicine, Rome, Italy.
Maurizio
M
Genuardi
Department of Pathology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
Riccardo
R
Fodde
Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
Alfonso
A
Bellacosa
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D004252:DNA Mutational Analysis; D004706:Endodeoxyribonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction
D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human; C492249:Mbd4 protein, mouse
HNPCC; MBD4/MED1; colorectal cancer; mismatch repair; mutations