Advances in the genetics of glioblastoma: are we reaching critical mass?

Abstract

Glioblastoma is the most common and highest-grade brain tumor, causing over 10,000 deaths each year in the US alone. Given the resistance of this tumor to standard surgery, radiation and chemotherapy, an understanding of the underlying genetic lesions is vital. Recent efforts to comprehensively profile glioblastomas using the latest technologies, both by The Cancer Genome Atlas (TCGA) project and by other groups, are addressing this need. Some genetic aberrations in glioblastoma have been known for decades, but early output from the new profiling initiatives has further illuminated the relevant genetics in this disease. Some genetic lesions, such as TP53 mutation, NF1 deletion or mutation, and ERBB2 amplification, have been found to be more common than was previously reported. New and unexpected discoveries have also been made, such as frequent mutations of the IDH1 and IDH2 genes in secondary glioblastoma. We might be tempted to speculate that we are approaching a comprehensive knowledge of the genetic lesions involved in glioblastoma, although other major discoveries doubtless remain to be made. In addition, the complex task of incorporating our updated knowledge into new--and possibly personalized--therapies for patients with glioblastoma still lies ahead.

Figure 1

Products of prominent oncogenes and tumor suppressor genes in glioblastoma. Oncogene products are shown as green arrows and tumor suppressors are depicted as red octagons. Approximate frequencies of genetic lesions in glioblastoma are included for each oncogene or tumor suppressor gene. Abbreviations: 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; amp, amplification; CDK4, cyclin-dependent kinase 4; CDKN2A, cyclin-dependent kinase inhibitor 2A; del, deletion; E2F1, transcription factor E2F1; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; HER2, human epidermal growth factor receptor 2; IDH, isocitrate dehydrogenase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; mut, mutation; NF1, neurofibromin 1; p70S6K, p70S6 kinase; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RB, retinoblastoma-associated protein.