Abstract
Brain tumors are currently diagnosed on the basis of their histology. The most common types in adults are astrocytomas, oligodendrogliomas and oligoastrocytomas or mixed tumors, which almost invariably lead to death. Improvements in outcome have been elusive despite intensive research. Recent findings indicate that response to conventional therapy, at least in some cases, correlates better with genetic characteristics than histopathology. An understanding of the molecular mechanisms that underlie the malignant phenotype of gliomas also provides the possibility of rational design of molecularly targeted therapies. This approach has proved successful in other areas of oncology. As many tumors have the same types of molecular abnormalities, molecular targeted therapies developed for nonbrain tumor types might be adapted for the treatment of brain tumors. There are a number of unique problems involved in treating tumors in the brain that must be overcome. The genetic predictors of response to conventional therapies, the genes and cellular mechanisms involved in glioma development, and potential therapeutic targets are reviewed. The possibility of designing tailored molecular therapy based on the molecular characteristics of the tumors is also explored.
Key Points
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Patients with tumors that have hemizygous loss of 1p and 19q chromosomal arms have a survival advantage, which might be a predictor of response to conventional treatment with irradiation and alkylating agents
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Methylation of MGMT in glioblastomas seems to predict a good response to alkylating agents, particularly temozolomide
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Genetic and transcriptome studies indicate that technologies assessing global genetic changes and gene expression in brain tumors may provide information relevant for prognostication (prognostic indicators) and choice of therapy (therapy response indicators)
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The introduction of molecularly targeted therapies will obligate a molecular (i.e. genetic and/or expression) analysis of tumor tissue to help determine the appropriate therapy in an individual case
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Combinations of molecularly targeted therapies with or without conventional therapies are likely to be required for success
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References
Hegi ME et al. (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352: 997–1003
Carlson RW et al. (2006) NCCN Task Force Report: adjuvant therapy for breast cancer. J Natl Compr Canc Netw 4 (Suppl 1): S1–S26
Tauchi T and Ohyashiki K (2006) The second generation of BCR-ABL tyrosine kinase inhibitors. Int J Hematol 83: 294–300
Schwartzbaum JA et al. (2006) Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol 2: 494–503
Corn B et al. (1994). Malignant oligodendroglioma arising after radiation therapy for lymphoma. Med Pediatr Oncol 22: 45–52
Rollison DE et al. (2005) Investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories. Int J Cancer 113: 769–774
Kleihues P et al. (1995) Genetic and environmental factors in the etiology of human brain tumors. Toxicol Lett 82–83: 601–605
Malmer B et al. (2001) Genetic epidemiology of glioma. Br J Cancer 84: 429–434
Kleihues P and Cavenee WK (2000) Pathology and Genetics of Tumours of the Nervous System. Lyon: International Agency for Research on Cancer (series eds Kleihues P and Sobin LH)
Breedveld P et al. (2005) The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res 65: 2577–2582
Schinkel AH (1999) P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 36: 179–194
Kleihues P and Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-oncol 1: 44–51
McCormack BM et al. (1992) Treatment and survival of low-grade astrocytoma in adults—1977–1988. Neurosurgery 31: 636–642
Vertosick FT Jr et al. (1991) Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography. Neurosurgery 28: 496–501
Stupp R et al. (2005) Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep 5: 198–206
Perry A et al. (1999) Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors: an analysis of DNA content (ploidy), cellular proliferation, and p53 expression. Cancer 86: 672–683
Rasheed A et al. (2000) Molecular markers of prognosis in astrocytic tumors. Cancer 94: 2688–2697
Smith JS et al. (2001) PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93: 1246–1256
Ichimura K et al. (2000) Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res 60: 417–424
James CD et al. (1989) Mitotic recombination of chromosome 17 in astrocytomas. Proc Natl Acad Sci USA 86: 2858–2862
Koschny R et al. (2002) Comparative genomic hybridization in glioma: a meta-analysis of 509 cases. Cancer Genet Cytogenet 135: 147–159
Hermanson M et al. (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52: 3213–3219
Ekstrand AJ et al. (1991) Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 51: 2164–2172
Ohgaki H and Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64: 479–489
von Deimling A et al. (2000) Comprehensive allelotype and genetic anaysis of 466 human nervous system tumors. J Neuropathol Exp Neurol 59: 544–558
von Deimling A et al. (1994) Loci associated with malignant progression in astrocytomas: a candidate on chromosome 19q. Cancer Res 54: 1397–1401
Backlund LM et al. (2005) Mutations in Rb1 pathway-related genes are associated with poor prognosis in anaplastic astrocytomas. Br J Cancer 93: 124–130
Ohgaki H et al. (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64: 6892–6899
Reifenberger J et al. (1996) Analysis of p53 mutation and epidermal growth factor receptor amplification in recurrent gliomas with malignant progression. J Neuropathol Exp Neurol 55: 822–831
Reifenberger G et al. (1993) Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res 53: 2736–2739
Riemenschneider MJ et al. (1999) 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
Sherr CJ and McCormick F (2002) The RB and p53 pathways in cancer. Cancer Cell 2: 103–112
Schmidt EE et al. (1994) CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 54: 6321–6324
Reifenberger G et al. (1994) 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
Buschges R et al. (1999) Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. Brain Pathol 9: 435–442; discussion 432–433
Ichimura K et al. (1996) Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. Oncogene 13: 1065–1072
Ichimura K et al. (2004) Molecular pathogenesis of astrocytic tumours. J Neurooncol 70: 137–160
Nakamura M et al. (2001) Promoter hypermethylation of the RB1 gene in glioblastomas. Lab Invest 81: 77–82
Biernat W et al. (1997) Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. Acta Neuropathol (Berl) 94: 303–309
Libermann TA et al. (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313: 144–147
Liu L et al. (2005) Clinical significance of EGFR amplification and the aberrant EGFRvIII transcript in conventionally treated astrocytic gliomas. J Mol Med 83: 917–926
Okada Y et al. (2003) Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas. Cancer Res 63: 413–416
Liu L et al. (2000) The complexity of the 7p12 amplicon in human astrocytic gliomas: detailed mapping of 246 tumors. J Neuropathol Exp Neurol 59: 1087–1093
Huang HS et al. (1997) The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem 272: 2927–2935
Collins VP (1995) Gene amplification in human gliomas. Glia 15: 289–296
Fleming TP et al. (1992) Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 52: 4550–4553
Knobbe CB et al. (2004) Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol (Berl) 108: 467–470
Steck PA et al. (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15: 356–362
Schmidt E et al. (1999) Mutational profile of the PTEN/MMAC1 gene in primary human astrocytic tumors and xenografts. J Neuropathol Exp Neurol 58: 1170–1183
Knobbe CB and Reifenberger G (2003) Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3′-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 13: 507–518
Samuels Y et al. (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554
Knobbe CB et al. (2005) Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3 CA and PIKE in human glioblastomas. Neuropathol Appl Neurobiol 31: 486–490
Knobbe CB et al. (2004) Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Inst 96: 483–486
Rubio-Viqueira B and Hidalgo M (2006) Targeting mTOR for cancer treatment. Curr Opin Investig Drugs 7: 501–512
Backlund LM et al. (2003) Short postoperative survival for glioblastoma patients with a dysfunctional Rb1 pathway in combination with no wild-type PTEN. Clin Cancer Res 9: 4151–4158
Tso CL et al. (2006) Distinct transcription profiles of primary and secondary glioblastoma subgroups. Cancer Res 66: 159–167
Phillips HS et al. (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9: 157–173
Cairncross JG and Macdonald DR (1988) Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 23: 360–364
Reifenberger J et al. (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145: 1175–1190
Griffin CA et al. (2006) Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 65: 988–994
Jenkins RB et al. (2006) A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 66: 9852–9861
Cairncross JG et al. (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90: 1473–1479
Cairncross G et al. (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24: 2707–2714
van den Bent MJ et al. (2006) Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24: 2715–2722
Mollemann M et al. (2005) Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer 113: 379–385
Idbaih A et al. (2005) Two types of chromosome 1p losses with opposite significance in gliomas. Ann Neurol 58: 483–487
Reifenberger G and Louis DN (2003) Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol 62: 111–126
Wolter M et al. (2001) Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes. J Neuropathol Exp Neurol 60: 1170–1180
Cully M et al. (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6: 184–192
Shaw RJ and Cantley LC (2006) Ras, PI(3) K and mTOR signalling controls tumour cell growth. Nature 441: 424–430
Yohay KH (2006) The genetic and molecular pathogenesis of NF1 and NF2. Semin Pediatr Neurol 13: 21–26
Galiatsatos P and Foulkes WD (2006) Familial adenomatous polyposis. Am J Gastroenterol 101: 385–398
Hamilton SR et al. (1995) The molecular basis of Turcot's syndrome. N Engl J Med 332: 839–847
Lackner C and Hoefler G (2005) Critical issues in the identification and management of patients with hereditary non-polyposis colorectal cancer. Eur J Gastroenterol Hepatol 17: 317–322
Ess KC (2006) The neurobiology of tuberous sclerosis complex. Semin Pediatr Neurol 13: 37–42
Inoki K et al. (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37: 19–24
Ino Y et al. (2000) Mutation analysis of the hCHK2 gene in primary human malignant gliomas. Neurogenetics 3: 45–46
Varley J (2003) TP53, hChk2, and the Li-Fraumeni syndrome. Methods Mol Biol 222: 117–129
Sansal I and Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22: 2954–2963
Greene MH (1999) The genetics of hereditary melanoma and nevi. 1998 update. Cancer 86: 2464–2477
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Collins, V. Mechanisms of Disease: genetic predictors of response to treatment in brain tumors. Nat Rev Clin Oncol 4, 362–374 (2007). https://doi.org/10.1038/ncponc0820
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DOI: https://doi.org/10.1038/ncponc0820
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