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glioblastoma_multiforme_genomic_alterations

Glioblastoma multiforme genomic alterations

Glioblastoma Multiforme (GBM) genetic analysis has become integral for classification and determination of prognosis 1) 2) 3).

Genetic mapping of the GBM genome has unveiled countless significantly mutated genes; although many of these mutations contribute to glioma progression, therapeutic-specific modalities require further investigation 4) 5) 6).

Several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer 7).


Genomewide mutational analysis of glioblastomas revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas).

Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas 8).

1)
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3)
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4)
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5)
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008 Oct 23;455(7216):1061-8. doi: 10.1038/nature07385. Epub 2008 Sep 4. Erratum in: Nature. 2013 Feb 28;494(7438):506. PubMed PMID: 18772890; PubMed Central PMCID: PMC2671642.
6)
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008 Sep 26;321(5897):1807-12. doi: 10.1126/science.1164382. Epub 2008 Sep 4. PubMed PMID: 18772396; PubMed Central PMCID: PMC2820389.
7)
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8)
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009 Feb 19;360(8):765-73. doi: 10.1056/NEJMoa0808710. PubMed PMID: 19228619; PubMed Central PMCID: PMC2820383.
glioblastoma_multiforme_genomic_alterations.txt · Last modified: 2018/03/12 13:44 by administrador