Avances en biología molecular en gliomas de alto grado

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1 Avances en biología molecular en gliomas de alto grado Dra. Avelina Tortosa Campus Ciencies de la Salut Bellvitge IDIBELL-Universitat de Barcelona

2 Goal: to profile a large cohort of GBMs (approximately 500) at the DNA, mrna, microrna, and epigenetics (DNA methylation) levels.

3 The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455:

4 The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455:

5 The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455:

6 The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455:

7 The Cancer Genome Atlas (TCGA) Research Network. Nature 2008; 455:

8 Verhaak RGW et al. Cancer Cell 2010; 17:

9 Verhaak RGW et al. Cancer Cell 2010; 17:

10 Parsons et al. SCIENCE; 2008; 321:1807

11 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

12 IDH1/2 mutation Similar studies found acute myeloid leukemias (8%) Non-R132H IDH1 mutations Greater proportion of IDH2 than IDH1 mutations

13 IDH1/2 mutation: association with other genetic changes IDH1/2 mutations: Associated with TP53 mutations 1p/19q codeletion MGMT promoter methylation

14 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

15 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:

16 IDH1/2 mutation as prognostic marker

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18 IDH1/2 mutation as prognostic marker

19 IDH1/2 mutation and gliomagenesis

20 Gupta R et al. J Clin Pathol 2011;64:835-

21 Gupta R et al. J Clin Pathol 2011;64:835-

22 Phillips HE et al. Cancer Cell 2006; 9: Verhaak RGW et al. Cancer Cell 2010; 17:

23 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:

24 IDH1/2 mutation and G-CIMP Noushmehr et al. Cancer Cell 2010; 17:

25 IDH1/2 mutation and G-CIMP

26 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

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28 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.

29 Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011

30 Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011

31 Serum YKL-40 values in patients with evidence of radiographic disease P = Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011

32 Serum YKL-40 values and radiographic disease Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011

33 ltivariate analysis including standard prognostic factors and serum YKL Iwamoto et al.: Serum YKL-40 in gliomas. Neuro-Oncology, 2011

34 Overall survival curves for newly diagnosed GBM HR = 1.2; 95% , p = 0.03

35 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?

36 Avances en biología molecular en gliomas de alto grado Dra. Avelina Tortosa Campus Ciencies de la Salut Bellvitge IDIBELL-Universitat de Barcelona