PTEN mutations in gliomas and glioneuronal tumors

Abstract

Cytogenetic and loss of heterozygosity studies have suggested the presence of at least one tumor suppressor gene on chromosome 10 involved in the formation of high grade gliomas. Recently, the PTEN gene, also termed MMAC1 or TEP1, on chromosomal band 10q23 has been identi®ed. Initial studies revealed mutations of PTEN in limited series of glioma cell lines and glioblastomas. In order to systematically evaluate the involvement of PTEN in gliomas, we have analysed the entire PTEN coding sequence by SSCP and direct sequencing in a series of 331 gliomas and glioneuronal tumors. PTEN mutations were detected in 20/142 glioblastomas, 1/7 giant cell glioblastomas, 1/2 gliosarcomas, 1/30 pilocytic astrocytomas and 2/22 oligodendrogliomas. No PTEN mutations were detected in 52 astrocytomas, 37 oligoastrocytomas, three subependymal giant cell astrocytomas, four pleomorphic xanthoastrocytomas, 15 ependymomas, 16 gangliogliomas and one dysembryoplastic neuroepithelial tumor. In addition, all tumors were examined for the presence of homozygous deletions of the PTEN gene; these were detected in 7 glioblastomas that did not have PTEN mutations. Therefore, PTEN mutations occur in approximately 20% of glioblastomas but are rare in lower grade gliomas. These ®ndings con®rm that PTEN is one of the chromosome 10 tumor suppressor genes involved in the development of glioblastomas.

Genetic abnormalities detected in ependymomas by comparative genomic hybridisation

“…Loss of part or most of chromosome 10 is common in glioblastomas, and many of them also harbour mutations of the PTEN tumour suppressor gene at 10q23 (Bostrom et al, 1998;Duerr et al, 1998). Abnormalities of chromosome 10 appear less commonly in ependymomas, but among spinal tumours in our series clearly differentiate classic tumours from myxopapillary tumours.…”

“…Abnormalities of chromosome 10 appear less commonly in ependymomas, but among spinal tumours in our series clearly differentiate classic tumours from myxopapillary tumours. Microsatellite analysis has shown loss of 10q to be uncommon in ependymomas, and no mutation of the PTEN gene has been reported (Duerr et al, 1998;Ebert et al, 1999;Tong et al, 1999).…”

The role of PTEN signaling perturbations in cancer and in targeted therapy

“…Among these mutations are structural rearrangements within the PTEN gene (intragenic inversions, insertions, deletions and duplications known as gross PTEN mutations) that occur in BRCA1-associated basal-like breast cancer (Saal et al, 2008). PTEN mutation frequencies affecting both alleles in various cancers are: endometrial (B50%), glioblastoma (B30%), prostate (B10%), and breast (B5%) (Cairns et al, , 1998Steck et al, 1997;Tashiro et al, 1997;Wang et al, 1997;Chiariello et al, 1998;Duerr et al, 1998;Lin et al, 1998;Shao et al, 1998;Ali et al, 1999;Zhou et al, 2002;Saal et al, 2005). The monoalleleic loss of PTEN is regularly observed in a considerable fraction of malignancies at the following frequencies: glioma (B75%), breast (B40-50%), colon (B20%), lung (B37%), prostate (B42%) (Teng et al, 1997;Bose et al, 1998;Feilotter et al, 1998;Lin et al, 1998;Rubin et al, 2000).…”

“…Sequencing of the PTEN gene in tumors found it to be one of the most commonly mutated tumor suppressors in human malignancies Rasheed et al, 1997;Tashiro et al, 1997;Wang et al, 1997Wang et al, , 1998Cairns et al, 1998;Duerr et al, 1998;Shao et al, 1998). The hereditary loss of PTEN leads to numerous autosomal dominant disorders: Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome and Proteuslike syndrome, which are characterized by the presence of developmental defects, benign hamartomas and an increased risk of cancer Marsh et al, 1997;Zhou et al, 2000Zhou et al, , 2001.…”

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma

“…With respect to chromosomal aberrations deletions of 1p, 9p, 10, 13q, 17p, 19q, and 22q, and gains of chromosome 7 ( Liu et al, 1997;Rasheed et al, 1997;Duerr et al, 1998;Smith and Jenkins, 2000) are the most common in gliomas. Several genes have been identified to be associated with tumorigenesis and anaplastic progression of glioblastoma subgroups including, besides the already mentioned p16/Cdkn2/Ink4, EGFR, PTEN, p53, and HDM2 also for example cdk4, cyclin D1, PDGFRa, k-ras, N-myc, gli, c-myc, and myb (Mao and Hamoudi, 2000;Zhu and Parada, 2002).…”