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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.

Key Points

  • Glioblastoma is the most common and lethal brain tumor

  • Given the resistance of glioblastoma to standard therapies, an understanding of the genetic underpinnings of this cancer is crucial

  • New reports from high-throughput profiling efforts, such as The Cancer Genome Atlas, have contributed to a more comprehensive understanding of the genetic aberrations that drive glioblastoma

  • This influx of new data has blurred some of the classic genetic distinctions between primary and secondary glioblastoma, such as the association of TP53 mutations with secondary glioblastomas

  • New characteristics, such as IDH1 or IDH2 mutations in a majority of secondary glioblastomas, have been identified

  • Genetic findings are beginning to influence the application of treatments to patients with glioblastoma

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Figure 1: Products of prominent oncogenes and tumor suppressor genes in glioblastoma.

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Purow, B., Schiff, D. Advances in the genetics of glioblastoma: are we reaching critical mass?. Nat Rev Neurol 5, 419–426 (2009). https://doi.org/10.1038/nrneurol.2009.96

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