Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines.
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.
Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
N
N
Ishii
D
D
Maier
A
A
Merlo
M
M
Tada
Y
Y
Sawamura
A C
AC
Diserens
E G
EG
Van Meir
D000328:Adult; D000368:Aged; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D016147:Genes, Tumor Suppressor / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009385:Neoplastic Processes; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017354:Point Mutation; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion; D012737:Sex Factors; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D019941:Cyclin-Dependent Kinase Inhibitor p16; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human