title: A novel germline mutation of PTEN associated with brain tumours of multiple lineages.
abstract: 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.
authors.affiliation: Department of Immunology, Erasmus University Rotterdam, Rotterdam, The Netherlands. f.j.t.staal@immu.fgg.eur.nl
authors.forename: F J T
authors.initials: FJ
authors.lastname: Staal
authors.forename: R B
authors.initials: RB
authors.lastname: van der Luijt
authors.forename: M R M
authors.initials: MR
authors.lastname: Baert
authors.forename: J
authors.initials: J
authors.lastname: van Drunen
authors.forename: H
authors.initials: H
authors.lastname: van Bakel
authors.forename: E
authors.initials: E
authors.lastname: Peters
authors.forename: I
authors.initials: I
authors.lastname: de Valk
authors.forename: H K P
authors.initials: HK
authors.lastname: van Amstel
authors.forename: M J B
authors.initials: MJ
authors.lastname: Taphoorn
authors.forename: G H
authors.initials: GH
authors.lastname: Jansen
authors.forename: C W M
authors.initials: CW
authors.lastname: van Veelen
authors.forename: B
authors.initials: B
authors.lastname: Burgering
authors.forename: G E J
authors.initials: GE
authors.lastname: Staal
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D019070:Cell Lineage; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005625:Frontal Lobe / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D019656:Loss of Heterozygosity; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000473:pathology; D008579:Meningioma / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000473:pathology; D009837:Oligodendroglioma / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017354:Point Mutation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D020298:U937 Cells / Q000187:drug effects / Q000201:enzymology
chemical_list: D004273:DNA, Neoplasm; D007328:Insulin; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human