A novel germline mutation of PTEN associated with brain tumours of multiple lineages
F J T Staal1, R B van der Luijt, M R M Baert
1Department of Immunology, Erasmus University Rotterdam, Rotterdam, The Netherlands. f.j.t.staal@immu.fgg.eur.nl
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.
Insights
A novel PTEN gene mutation (Arg234Gln) was found in a patient with glioma. This mutation promotes cell growth and brain tumor development, even without Cowden disease signs.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Germline mutations in tumour suppressor genes, such as PTEN, are linked to hereditary cancer syndromes.
- PTEN (Phosphatase and tensin homolog) plays a critical role in cell growth, proliferation, and apoptosis.
Observation:
- A novel heterozygous germline mutation PTEN (Arg234Gln) was identified in a patient diagnosed with glioma.
- The patient had a history of meningioma but lacked typical clinical features of Cowden disease.
Findings:
- Transfection studies revealed the mutant PTEN protein impairs apoptosis and enhances cell proliferation.
- The Arg234Gln mutation results in constitutive activation of PKB/Akt signaling, independent of insulin stimulation.
Implications:
- The Arg234Gln PTEN mutation exhibits oncogenic properties, contributing to brain tumor development.
- This finding suggests PTEN mutations can predispose individuals to multiple brain tumor types, irrespective of classic Cowden disease phenotypes.
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