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
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Glioblastoma is the most common and lethal brain tumor
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Given the resistance of glioblastoma to standard therapies, an understanding of the genetic underpinnings of this cancer is crucial
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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
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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
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New characteristics, such as IDH1 or IDH2 mutations in a majority of secondary glioblastomas, have been identified
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Genetic findings are beginning to influence the application of treatments to patients with glioblastoma
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References
CBTRUS: Statistical report: primary brain tumors in the United States, 1998–2002 (Central Brain Tumor Registry of the United States, 2008).
Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).
Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).
Wilson, C. B., Kaufmann, L. & Barker, M. Chromosome analysis of glioblastoma multiforme. Neurology 20, 821–828 (1970).
Mark, J. & Granberg, I. The chromosomal aberration of double-minutes in three gliomas. Acta Neuropathol. 16, 194–204 (1970).
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Libermann, T. A. et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313, 144–147 (1985).
Nishikawa, R. et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc. Natl Acad. Sci. USA 91, 7727–7731 (1994).
Ekstrand, A. J. et al. Genes for epidermal growth factor receptor, transforming growth factor α, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 51, 2164–2172 (1991).
Prados, M. D. et al. Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro. Oncol. 8, 67–78 (2006).
Haas-Kogan, D. A. et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J. Natl Cancer Inst. 97, 880–887 (2005).
Sorensen, S. A., Mulvihill, J. J. & Nielsen, A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N. Engl. J. Med. 314, 1010–1015 (1986).
Xu, G. F. et al. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63, 835–841 (1990).
Li, Y. et al. Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell 69, 275–281 (1992).
Fleming, T. P. et al. Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res. 52, 4550–4553 (1992).
Koochekpour, S. et al. Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res. 57, 5391–5398 (1997).
Stommel, J. M. et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318, 287–290 (2007).
Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat. Genet. 25, 55–57 (2000).
Liu, W., James, C. D., Frederick, L., Alderete, B. E. & Jenkins, R. B. PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. Cancer Res. 57, 5254–5257 (1997).
Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).
Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).
Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutations in human cancers. Science 253, 49–53 (1991).
Dittmer, D. et al. Gain of function mutations in p53. Nat. Genet. 4, 42–46 (1993).
Halevy, O., Michalovitz, D. & Oren, M. Different tumor-derived p53 mutants exhibit distinct biological activities. Science 250, 113–116 (1990).
Momand, J., Zambetti, G. P., Olson, D. C., George, D. & Levine, A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69, 1237–1245 (1992).
Honda, R., Tanaka, H. & Yasuda, H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 420, 25–27 (1997).
He, J., Reifenberger, G., Liu, L., Collins, V. P. & James, C. D. Analysis of glioma cell lines for amplification and overexpression of MDM2. Genes Chromosomes Cancer 11, 91–96 (1994).
Reifenberger, G., Liu, L., Ichimura, K., Schmidt, E. E. & Collins, V. P. Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res. 53, 2736–2739 (1993).
Riemenschneider, M. J. et al. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res. 59, 6091–6096 (1999).
Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).
Zhang, Y., Xiong, Y. & Yarbrough, W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92, 725–734 (1998).
Schmidt, E. E., Ichimura, K., Reifenberger, G. & Collins, V. P. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res. 54, 6321–6324 (1994).
Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).
Flemington, E. K., Speck, S. H. & Kaelin, W. G. Jr. E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc. Natl Acad. Sci. USA 90, 6914–6918 (1993).
Wiedemeyer, R. et al. Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development. Cancer Cell 13, 355–364 (2008).
Solomon, D. A. et al. Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme. Cancer Res. 68, 2564–2569 (2008).
Ichimura, K., Schmidt, E. E., Goike, H. M. & Collins, V. P. Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. Oncogene 13, 1065–1072 (1996).
Reifenberger, G., Reifenberger, J., Ichimura, K., Meltzer, P. S. & Collins, V. P. Amplification of multiple genes from chromosomal region 12q13–14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. Cancer Res. 54, 4299–4303 (1994).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Reifenberger, G., Reifenberger, J., Ichimura, K. & Collins, V. P. Amplification at 12q13–14 in human malignant gliomas is frequently accompanied by loss of heterozygosity at loci proximal and distal to the amplification site. Cancer Res. 55, 731–734 (1995).
Rey, J. A. et al. Chromosomal patterns in human malignant astrocytomas. Cancer Genet. Cytogenet. 29, 201–221 (1987).
James, C. D. et al. Chromosome 9 deletion mapping reveals interferon α and interferon β-1 gene deletions in human glial tumors. Cancer Res. 51, 1684–1688 (1991).
Bigner, S. H. et al. Specific chromosomal abnormalities in malignant human gliomas. Cancer Res. 48, 405–411 (1988).
Bello, M. J. et al. Molecular analysis of chromosome 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors. Int. J. Cancer 57, 172–175 (1994).
Freire, P. et al. Exploratory analysis of the copy number alterations in glioblastoma multiforme. PLoS ONE 3, e4076 (2008).
Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).
Yan, L. X. et al. MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 14, 2348–2360 (2008).
Bandres, E. et al. Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol. Cancer 5, 29 (2006).
Ciarapica, R. et al. Deregulated expression of miR-26a and Ezh2 in rhabdomyosarcoma. Cell Cycle 8, 172–175 (2009).
Nakamura, M. et al. Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas. Lab. Invest. 85, 165–175 (2005).
Nakamura, M. et al. Loss of heterozygosity on chromosome 19 in secondary glioblastomas. J. Neuropathol. Exp. Neurol. 59, 539–543 (2000).
Fujisawa, H. et al. Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. Lab. Invest. 80, 65–72 (2000).
Fujimoto, M. et al. Loss of heterozygosity on chromosome 10 in human glioblastoma multiforme. Genomics 4, 210–214 (1989).
James, C. D. et al. Clonal genomic alterations in glioma malignancy stages. Cancer Res. 48, 5546–5551 (1988).
Ohgaki, H. et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 64, 6892–6899 (2004).
Schwartzbaum, J. et al. Polymorphisms associated with asthma are inversely related to glioblastoma multiforme. Cancer Res. 65, 6459–6465 (2005).
Hamilton, S. R. et al. The molecular basis of Turcot's syndrome. N. Engl. J. Med. 332, 839–847 (1995).
Blumenthal, D. T. & Cannon-Albright, L. A. Familiality in brain tumors. Neurology 71, 1015–1020 (2008).
Liu, Y. et al. Tagging SNPs in non-homologous end-joining pathway genes and risk of glioma. Carcinogenesis 28, 1906–1913 (2007).
Liu, Y. et al. Polymorphisms of LIG4 and XRCC4 involved in the NHEJ pathway interact to modify risk of glioma. Hum. Mutat. 29, 381–389 (2008).
Bethke, L. et al. Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma. Hum. Mol. Genet. 17, 800–805 (2008).
Wrensch, M. et al. ERCC1 and ERCC2 polymorphisms and adult glioma. Neuro Oncol. 7, 495–507 (2005).
Bethke, L. et al. The common D302H variant of CASP8 is associated with risk of glioma. Cancer Epidemiol. Biomarkers Prev. 17, 987–989 (2008).
Rajaraman, P. et al. Polymorphisms in apoptosis and cell cycle control genes and risk of brain tumors in adults. Cancer Epidemiol. Biomarkers Prev. 16, 1655–1661 (2007).
Bethke, L. et al. Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma. Cancer Epidemiol. Biomarkers Prev. 17, 1195–1202 (2008).
Lai, R., Crevier, L. & Thabane, L. Genetic polymorphisms of glutathione S-transferases and the risk of adult brain tumors: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 14, 1784–1790 (2005).
De Roos, A. J. et al. Genetic polymorphisms in GSTM1, -P1, -T1, and CYP2E1 and the risk of adult brain tumors. Cancer Epidemiol. Biomarkers Prev. 12, 14–22 (2003).
Ezer, R. et al. Identification of glutathione S-transferase (GST) polymorphisms in brain tumors and association with susceptibility to pediatric astrocytomas. J. Neurooncol. 59, 123–134 (2002).
Scheurer, M. E. et al. Polymorphisms in the interleukin-4 receptor gene are associated with better survival in patients with glioblastoma. Clin. Cancer Res. 14, 6640–6646 (2008).
Scheurer, M. E. et al. Long-term anti-inflammatory and antihistamine medication use and adult glioma risk. Cancer Epidemiol. Biomarkers Prev. 17, 1277–1281 (2008).
Mellinghoff, I. K. et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024 (2005).
Lassman, A. B. et al. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01–03 and 00–01 Clin. Cancer Res. 11, 7841–7850 (2005).
Prados, M. D. et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J. Clin. Oncol. 27, 579–584 (2009).
Brown, P. D. et al. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J. Clin. Oncol. 26, 5603–5609 (2008).
Liu, L. & Gerson, S. L. Targeted modulation of MGMT: clinical implications. Clin. Cancer Res. 12, 328–331 (2006).
Hunter, C. et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66, 3987–3991 (2006).
Cahill, D. P. et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin. Cancer Res. 13, 2038–2045 (2007).
Zhou, X. P. et al. Germline mutations of p53 but not p16/CDKN2 or PTEN/MMAC1 tumor suppressor genes predispose to gliomas. The ANOCEF Group. Association des NeuroOncologues d'Expression Francaise. Ann. Neurol. 46, 913–916 (1999).
Watanabe, K. et al. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 6, 217–223 (1996).
Vahteristo, P. et al. p53, CHK2, and CHK1 genes in Finnish families with Li–Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 61, 5718–5722 (2001).
Watson, P. et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int. J. Cancer 123, 444–449 (2008).
Guillamo, J. S. et al. Prognostic factors of CNS tumours in neurofibromatosis 1 (NF1): a retrospective study of 104 patients. Brain 126, 152–160 (2003).
Gutmann, D. H. et al. Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1. Neurology 61, 1397–1400 (2003).
Bahuau, M. et al. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res. 58, 2298–2303 (1998).
Biernat, W., Kleihues, P., Yonekawa, Y. & Ohgaki, H. Amplification and overexpression of MDM2 in primary (de novo) glioblastomas. J. Neuropathol. Exp. Neurol. 56, 180–185 (1997).
Tohma, Y. et al. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J. Neuropathol. Exp. Neurol. 57, 684–689 (1998).
Saxena, A., Shriml, L. M., Dean, M. & Ali, I. U. Comparative molecular genetic profiles of anaplastic astrocytomas/glioblastomas multiforme and their subsequent recurrences. Oncogene 18, 1385–1390 (1999).
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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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DOI: https://doi.org/10.1038/nrneurol.2009.96
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