PTEN (MMAC1) Mutations Are Frequent in Primary Glioblastomas (de novo) but not in Secondary Glioblastomas

Abstract

Loss of heterozygosity (LOH) on chromosome 10 is the most frequent genetic alteration associated with the evolution of malignant astrocytic tumors and it may involve several loci. The tumor suppressor gene PTEN (MMAC1) on chromosome 10q23 is mutated in approximately 30% of glioblastomas (WHO Grade IV). In this study, we assessed the frequency of PTEN mutations in primary glioblastomas, which developed clinically de novo, and in secondary glioblastomas, which evolved from low-grade (WHO Grade II) or anaplastic astrocytomas (WHO Grade III). Nine of 28 (32%) primary glioblastomas contained a PTEN mutation and an additional case showed a homozygous PTEN deletion. This indicates that after overexpression/amplification of the EGF receptor, loss of PTEN function is the most common alteration in primary glioblastomas. In this series, 5 of 28 (18%) primary glioblastomas showed both a PTEN mutation and EGFR amplification. In contrast, only 1 of 25 (4%) secondary glioblastomas contained a PTEN mutation, and none of them showed a homozygous PTEN deletion. The secondary glioblastoma with a PTEN mutation developed from an anaplastic astrocytoma that already carried the mutation. The observation that secondary glioblastomas have a p53 mutation as a genetic hallmark but rarely contain a PTEN mutation supports the concept that primary and secondary glioblastomas develop differently on a genetic level.

PTEN signaling in brain: neuropathology and tumorigenesis

“…Primary GBM arises de novo, more often in older patients and without any pre-existing low-grade lesion, whereas secondary GBM develops progressively from lower-grade astrocytoma in patients who are generally younger at diagnosis (Louis et al, 2007). PTEN mutation occurs more frequently in primary tumors (25%) compared to secondary tumors (5%), although the rate of LOH at 10q is similar between the two groups (Tohma et al, 1998). The spectrum of PTEN mutations in GBM overlaps with that observed in PHTS patients, as well as other tumor types (Figure 2).…”

Comparison of automated silver enhanced in situ hybridization and fluorescence in situ hybridization for evaluation of epidermal growth factor receptor status in human glioblastomas

“…26,30,31 Although EGFR protein overexpression was highly associated with gene amplification, there were 29 of 64 cases that showed a high EGFR protein level and no EGFR amplification by fluorescence in situ hybridization or silver enhanced in situ hybridization. All cases with gene amplification showed immunohistochemistry positivity.…”

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

“…The primer sequences were as described previously (Yuen et al, 1997). (d) Ampli®cation of the EGFR gene was detected by the di erential PCR method with the cystic ®brosis (CF) gene as a reference, similar to the method described previously (Hunter et al, 1995;Tohma et al, 1998). After PCR and gel electrophoresis, the intensity of the EGFR fragment (110 bp) and CF reference fragment (79 bp) were measured by the GDS8000 Complete Gel Documentation and Analysis system (UV Products, Cambridge, UK).…”

“…In view of the reported association of EGFR ampli®cation with some sporadic glial tumours, we studied all three glioblastomas and two colorectal carcinomas for ampli®cation of this gene, using di erential PCR, with the cystic ®brosis (CF) gene as reference (Hunter et al, 1995;Tohma et al, 1998). EGFR ampli®cation was absent from all the tumours.…”