A novel germline mutation of PTEN associated with brain tumours of multiple lineages

• Published in: British journal of cancer 2002-05, Vol.86 (10), p.1586-1591
• Main Authors: Staal, F J T, van der Luijt, R B, Baert, M R M, van Drunen, J, van Bakel, H, Peters, E, de Valk, I, van Amstel, H K P, Taphoorn, M J B, Jansen, G H, van Veelen, C W M, Burgering, B, Staal, G E J
• Format: Article
• Language: English
• Subjects: Adult; Amino Acid Substitution; Apoptosis - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Cancer Research; Cell Division; Cell Lineage; DNA Mutational Analysis; DNA, Neoplasm - genetics; Drug Resistance; Enzyme Activation - drug effects; Epidemiology; Frontal Lobe - pathology; Genetic Predisposition to Disease; Genetics and Genomics; Germ-Line Mutation; Humans; Insulin - pharmacology; Loss of Heterozygosity; Male; Medical sciences; Meningeal Neoplasms - genetics; Meningeal Neoplasms - pathology; Meningioma - genetics; Meningioma - pathology; Models, Molecular; Molecular Medicine; Mutation, Missense; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neoplasms, Multiple Primary - genetics; Neoplasms, Multiple Primary - pathology; Neurology; Oligodendroglioma - genetics; Oligodendroglioma - pathology; Oncology; Phosphoric Monoester Hydrolases - chemistry; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - physiology; Point Mutation; Protein Conformation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Transfection; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - physiology; Tumors of the nervous system. Phacomatoses; U937 Cells - drug effects; U937 Cells - enzymology
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6600206

We have identified a novel germline mutation in the PTEN tumour suppressor gene. The mutation was identified in a patient with a glioma, and turned out to be a heterozygous germline mutation of PTEN (Arg234Gln), without loss of heterozygosity in tumour DNA. The biological consequences of this germline mutation were investigated by means of transfection studies of the mutant PTEN molecule compared to wild-type PTEN. In contrast to the wild-type molecule, the mutant PTEN protein is not capable of inducing apoptosis, induces increased cell proliferation and leads to high constitutive PKB/Akt activation, which cannot be increased anymore by stimulation with insulin. The reported patient, in addition to glioma, had suffered from benign meningioma in the past but did not show any clinical signs of Cowden disease or other hereditary diseases typically associated with PTEN germline mutations. The functional consequences of the mutation in transfection studies are consistent with high proliferative activity. Together, these findings suggest that the Arg234Gln missense mutation in PTEN has oncogenic properties and predisposes to brain tumours of multiple lineages.