Avances en biología molecular en gliomas de alto grado Dra. Avelina Tortosa Campus Ciencies de la Salut Bellvitge IDIBELL-Universitat de Barcelona atortosa@ub.edu
Goal: to profile a large cohort of GBMs (approximately 500) at the DNA, mrna, microrna, and epigenetics (DNA methylation) levels.
The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455: 1061-1068
The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455: 1061-1068
The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455: 1061-1068
The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455: 1061-1068
The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455: 1061-1068
Verhaak RGW et al. Cancer Cell 2010; 17: 98-110
Verhaak RGW et al. Cancer Cell 2010; 17: 98-110
Parsons et al. SCIENCE; 2008; 321:1807
IDH1/2 mutation Large-scale genomic study by the Centre for Genomic Application 12% displayed mutations in IDH1 gene IDH1 mutations are heterozygous with a wildtype allele 89.3% are G A with Arg His at amino acid residue 132 IDH2 mutations at aminoacid residue Arg172 Young patients Secondary GBM
IDH1/2 mutation Similar studies found acute myeloid leukemias (8%) Non-R132H IDH1 mutations Greater proportion of IDH2 than IDH1 mutations
IDH1/2 mutation: association with other genetic changes IDH1/2 mutations: Associated with TP53 mutations 1p/19q codeletion MGMT promoter methylation
IDH1/2 mutation: association with other genetic changes IDH1/2 mutations: Associated with TP53 mutations 1p/19q codeletion MGMT promoter methylation Inversely associated with: EGFR amplification CDKN2A/B homozygous deletion (p16 and p14) PTEN mutations Chromosome 10 loss Not increase frequency in progression to highergrade gliomas
IDH1/2 mutation as prognostic marker SCIENCE; 2008; 321:1807 1p/19q coledetion + IDH1/2 mut partial 1p/19q coleteion +IDH1/2 mut no 1p/19q codeletion and no IDH1/2 mutation Labussière M et al. Neurology 2010; 74: 1886-1890
IDH1/2 mutation as prognostic marker
IDH1/2 mutation as prognostic marker
IDH1/2 mutation and gliomagenesis
Gupta R et al. J Clin Pathol 2011;64:835-
Gupta R et al. J Clin Pathol 2011;64:835-
Phillips HE et al. Cancer Cell 2006; 9: 157-173 Verhaak RGW et al. Cancer Cell 2010; 17: 98-110
Proneural GBM PGFRA amplification IDH1/2 mutation PI3A/PI3R1 mutation TP53, CDKN2A, PTEN loss/mutation Proneural marker expression SOX, DCX,DLL3,ASCL1, TCF4 Oligodendrocytic marker expression PDGFRA, OLIG2, TCF3, NKX2-2 Pathways activation HIF PI3 kinase PDGFRA Características moleculares de gliomas de bajo grado y GBM secundario firma molecular oligodendrocítica Mejor supervivencia global Fenotipo metilador (G-CIMP) Verhaak Noushmehr RGWetetal.al.Cancer CancerCell Cell2010; 2010;17: 17:510-522 98-110
IDH1/2 mutation and G-CIMP Noushmehr et al. Cancer Cell 2010; 17: 510-522
IDH1/2 mutation and G-CIMP
Mesenchymal GBM NF1 loss/mutation TP53 loss/mutation PTEN loss/mutation no mutations IDH1 Overexpression: Mesenchymal markers: YKL40, MET Epithelial-to-mensenchymal transition markers: CD44, MERTK Pathways activation TNF superfamily NFKβ (TRADD, RELB, TNFRSF1A) Características moleculares de GBM de novo firma molecular astrocítica Sobreexpresión YKL-40
YKL-40 Glicoproteína secretada al espacio estracelular Asociada a proliferación en tejido conectivo y a neovascularizació Induce neovascularización en c. de mama, independiente de VEG En GBM: Estimula directamente angiogénesis Estimula VEGF y angiogénesis Radioterapia: aumenta YKL-40 Secretada al plasma. Puede determinarse mediante ELISA YKL-40 en plasma: pronóstico en C. ovario, melanoma, AML, C. mama y C. próstata metastático.
Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011
Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011
Serum YKL-40 values in patients with evidence of radiographic disease P = 0.003 0.83 Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011
Serum YKL-40 values and radiographic disease Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011
ltivariate analysis including standard prognostic factors and serum YKL Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011
Overall survival curves for newly diagnosed GBM HR = 1.2; 95% 1.0 1.4, p = 0.03
Summary IDH mutations are early and common events in development of gliomas. IDH mutations strongly predict favorable outcome in patients with high-grade gliomas IDH mutations is associated with G-CIMP phenotype IDH1 mutations, G-CIMP phenotype associated with proneural GBM The underlying mechanism of IDH mutations remains unknown Tumoral 2-Hidroxyglutarate levels: clinical biomarker? Mesenchymal GBM associated with high levels YKL-40 Serum YKL-40 levels: clinical biomarker?
Avances en biología molecular en gliomas de alto grado Dra. Avelina Tortosa Campus Ciencies de la Salut Bellvitge IDIBELL-Universitat de Barcelona atortosa@ub.edu