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

TLDR

Loss of heterozygosity on chromosome 10, often involving PTEN at 10q23, is the most frequent genetic alteration in malignant astrocytic tumors, with PTEN mutated in about 30 % of glioblastomas. The study assessed the frequency of PTEN mutations in primary glioblastomas that arise de novo versus secondary glioblastomas that evolve from lower‑grade astrocytomas. The authors examined PTEN mutation and deletion status in 28 primary and 25 secondary glioblastomas by sequencing and copy‑number analysis. PTEN mutations were found in 32 % of primary glioblastomas (18 % also showing EGFR amplification) and in only 4 % of secondary glioblastomas, with no homozygous deletions, underscoring distinct genetic pathways between primary and secondary tumors.

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 (MMACI) 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.