Genetic markers in glioblastoma: prognostic significance and future therapeutic implications

Glioblastoma multiforme (GBM) is the highest-grade infiltrative astrocytoma and also the most common. It is generally associated with a dismal prognosis (mean survival 11 months), yet individual patient survivals vary. Histologic parameters have had limited value in predicting survival among patients with GBM. The current view of GBM as a histopathologic entity consisting of several genetic subtypes raises the possibility that molecular alterations could be predictive of survival. Common genetic alterations in GBM include gene amplification of epidermal growth factor receptor (EGFR), mutations in the tumor suppressors TP53 and PTEN, and genetic losses on chromosome 10. Less common in GBMs is the combined loss of chromosomes 1p and 19q-a combination that has proven prognostically favorable in oligodendrogliomas. A recent article on prognostic factors in a series of 97 GBMs by Schmidt et al. finds that both TP53 mutations and young patient age at presentation are independent factors associated with a long survival. Loss of heterozygosity (LOH) of chromosome 10q was predictive of a poor outcome. Perhaps most intriguing, the finding of combined LOH of 1p and 19q, which was noted in only five GBMs, was associated with a significantly longer survival. Thus, combined losses of 1p and 19 may be associated with a favorable prognosis in a wider range of infiltrative gliomas that includes GBM. While these findings will be debated and need to be confirmed, it is clear that genotyping of infiltrative gliomas will be an important component of neuro-oncology in the future. Not only will genetic alterations offer prognostication, but they will also serve as targets for directed therapies. Treatments directed against tumors with EGFR amplification, TP53, mutations and PTEN mutations are being developed and tested in clinical trials. It remains to be seen if GBMs with 1p and 19q losses are chemosensitive in the same manner as oligodendrogliomas.