AETIOLOGY AND PATHOGENESIS OF GLIOBLASTOMA MULTIFORME (GBM)

No underlying cause has been identified for the majority of malignant gliomas.  The only established risk factor is exposure to ionizing radiation.

Hans Joachim Scherer proposed nearly seventy years ago  that GBM can either develop by dedifferentiation from a lower grade tumor (“secondary GBM”) or can arise “de novo” (“primary GBM”), thus he was the first to clearly distinguish primary and secondary glioblastomas (Peiffer and Kleihues, 1999) . These differences in clinical and molecular features of the two types of GBM hint at a distinct pathogenesis.

Glioblastomas are  characterized by multiple genetic and epigenetic alterations.

- Epidermal growth factor receptor (EGFR) amplification ( Biernat et al, 2004)

- PTEN mutations are typical for primary glioblastomas developing rapidly de novo (Baeza et al, 2003)

- TP53 mutations are frequent in the pathway leading to secondary glioblastomas developing usually from lower grade astrocytomas.

- Loss of heterozygosity (LOH) 10q is the most frequent abberation in both primary and secondary glioblastomas

- Altered expression levels of several microRNAs (Lawler and Chiocca, 2009;  Novakova et al, 2009)

- Epigenetic Mechanism: DNA methylation, or DNA hypomethylation, changes in the position of histone variants and changes in histone modifications (Nagarajan and Costello, 2009; Martinez et al, 2007; Martinez et al, 2007b; Martinez et al, 2007c; Martinez et al, 2009)