Frequent Co-Alterations of TP53, p16/CDKN2A, p14ARF, PTEN Tumor Suppressor Genes in Human Glioma Cell Lines.
Nobuaki Ishii
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois (CHUV), rue du Bugnon 5, CH-1011, Lausanne, Switzerland
Search for more papers by this authorDaniel Maier
Molecular Neuro-Oncology, Neurosurgery and Department of Research, University Hospital, Schanzenstr. 46, CH-4031 Basel, Switzerland
Search for more papers by this authorAdrian Merlo
Molecular Neuro-Oncology, Neurosurgery and Department of Research, University Hospital, Schanzenstr. 46, CH-4031 Basel, Switzerland
Search for more papers by this authorMitsuhiro Tada
Department of Neurosurgery, University of Hokkaido School of Medicine, Sapporo 060, Japan
Search for more papers by this authorYutaka Sawamura
Department of Neurosurgery, University of Hokkaido School of Medicine, Sapporo 060, Japan
Search for more papers by this authorAnnie-Claire Diserens
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois (CHUV), rue du Bugnon 5, CH-1011, Lausanne, Switzerland
Search for more papers by this authorCorresponding Author
Erwin G. Van Meir
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois (CHUV), rue du Bugnon 5, CH-1011, Lausanne, Switzerland
Laboratory of Molecular Neuro-Oncology, Department of Neurological Surgery and Winship Cancer Center, Emory University, Atlanta, Georgia 30322, USA
Erwin G. Van Meir, PhD, Associate Professor, Laboratory of Molecular Neuro-Oncology, Department of Neurologic Surgery and Winship Cancer Center, 1365 B Clifton Road NE, Emory University, Atlanta, Georgia 30322, USA; Tel.: 404 778-5227; Fax: 404 778-5240; E-mail: [email protected]Search for more papers by this authorNobuaki Ishii
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois (CHUV), rue du Bugnon 5, CH-1011, Lausanne, Switzerland
Search for more papers by this authorDaniel Maier
Molecular Neuro-Oncology, Neurosurgery and Department of Research, University Hospital, Schanzenstr. 46, CH-4031 Basel, Switzerland
Search for more papers by this authorAdrian Merlo
Molecular Neuro-Oncology, Neurosurgery and Department of Research, University Hospital, Schanzenstr. 46, CH-4031 Basel, Switzerland
Search for more papers by this authorMitsuhiro Tada
Department of Neurosurgery, University of Hokkaido School of Medicine, Sapporo 060, Japan
Search for more papers by this authorYutaka Sawamura
Department of Neurosurgery, University of Hokkaido School of Medicine, Sapporo 060, Japan
Search for more papers by this authorAnnie-Claire Diserens
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois (CHUV), rue du Bugnon 5, CH-1011, Lausanne, Switzerland
Search for more papers by this authorCorresponding Author
Erwin G. Van Meir
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois (CHUV), rue du Bugnon 5, CH-1011, Lausanne, Switzerland
Laboratory of Molecular Neuro-Oncology, Department of Neurological Surgery and Winship Cancer Center, Emory University, Atlanta, Georgia 30322, USA
Erwin G. Van Meir, PhD, Associate Professor, Laboratory of Molecular Neuro-Oncology, Department of Neurologic Surgery and Winship Cancer Center, 1365 B Clifton Road NE, Emory University, Atlanta, Georgia 30322, USA; Tel.: 404 778-5227; Fax: 404 778-5240; E-mail: [email protected]Search for more papers by this authorAbstract
In this study we established the simultaneous status of TP53, p16, p14ARF and PTEN tumor suppressor genes in 34 randomly chosen human glioma cell lines. Nine cell lines (26.4%) harbored mutations or deletions in all four tumor suppressor genes and 22 cell lines (64%) had alterations in at least three. Mutations/deletions were found at the following frequencies: TP53 (76.5%), p14ARF (64.7%), p16 (64,7%), PTEN (73.5%). Thus, there was a high incidence of alterations in the cellular pathways involving the p53 transcription factor (94.1%), the retinoblastoma protein (64.7%) and the PTEN phosphatase (73.5%) and 91% of cell lines carried mutations in two or more pathways. This provides the first clear genetic evidence that these tumor suppressors participate in biological pathways which are functioning separately/independently in glioma cells. The status of the gene alterations did not correlate with tumorigenicity in immunocompromized mice or any clinical parameters. Although the mutation rate was higher in glioma cell lines than that reported for glioma tissues, the alterations were molecularly representative of those found in adult de novo glioblastoma. This study highlights the importance of developing therapeutic approaches applicable to tumors with a broad range of genetic alterations and also provides an invaluable panel of glioma cell lines to make this possible.
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