Research Papers:
Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis
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Abstract
Rossella Tricarico1, Salvatore Cortellino2, Antonio Riccio3, Shantie Jagmohan-Changur4, Heleen Van der Klift5, Juul Wijnen5, David Turner6, Andrea Ventura7, Valentina Rovella8, Antonio Percesepe9, Emanuela Lucci-Cordisco10, Paolo Radice11, Lucio Bertario11, Monica Pedroni12, Maurizio Ponz de Leon12, Pietro Mancuso1,13, Karthik Devarajan14, Kathy Q. Cai15, Andres J.P. Klein-Szanto15, Giovanni Neri10, Pål Møller16, Alessandra Viel17, Maurizio Genuardi10, Riccardo Fodde4, Alfonso Bellacosa1
1Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States
2IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
3Department of Cardiology, Boston Children’s Hospital, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, United States
4Department of Pathology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands
5Department of Clinical Genetics and Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
6Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
7Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York City, New York, United States
8Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
9Medical Genetics Unit, Department of Mother & Child, University Hospital of Modena, Modena, Italy
10Institute of Medical Genetics, Catholic University of the Sacred Heart, “A. Gemelli” School of Medicine, Rome, Italy
11Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
12Department of Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
13Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
14Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States
15Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States
16Inherited Cancer Research Group, Department for Medical Genetics, The Norwegian Radium Hospital, University Hospital, Oslo, Norway
17Experimental Oncology 1, CRO Aviano, National Cancer Institute, Aviano (PN), Italy
Correspondence to:
Alfonso Bellacosa, e-mail: [email protected]
Keywords: MBD4/MED1, HNPCC, colorectal cancer, mismatch repair, mutations
Received: June 10, 2015 Accepted: September 18, 2015 Published: October 16, 2015
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.
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