Morphological features and genetic alterations Tutor : Audrey Rousseau Caget Lise: Université d Angers Iorio Vittoria: Seconda Università degli studi di Napoli Manaila Roxana: Iuliu Hatieganu University of Medicine and Pharmacy Pommier Kévin: Université de Nantes Pozsgai Zsuzsa: University of Szeged
Introduction Definitions WHO classification Astrocytomas Morphological features Genetic alterations Oligodendrogliomas Morphological features Genetic alterations Oligoastrocytomas Morphological features Therapy Conclusion
Most frequent primary brain tumors Different types according their similarities to glial cells: Ependymoma Circumscribed Glioma Astrocytoma Mixed Oligoastrocytoma Diffuse Gliomas ++ Oligodendroglioma
Histological (morphological) classification Tumors are graded on a scale of II to IV Increasing grade meaning increasing malignancy
Neural stem-cell Glial progenitor Primary (de novo) GBM Diffuse Astrocytoma Anaplastic astrocytoma Secondary GBM Premalignant cells? Oligoastrocytoma Anaplastic Oligoastrocytoma GBM-O Oligodendroglioma Anaplastic oligodendroglioma? Grade II Grade III Anaplastic transformation Grade IV
mild to moderate increase in cellularity (2-3 times) moderate nuclear pleomorphism low mitotic activity intercellular oedema cystic degeneration no neoangiogenesis no necrosis
Same histopathological features + signs of focal or diffuse anaplasia show high cell density nuclear pleomorphism mitoses are easily found no neoangiogenesis no necrosis
Morphology may be extremely heterogeneous: from small round tumor cells to multinucleated giant cells Poorly differentiated neoplastic astrocytes Cellular and nuclear pleomorphisms Mitoses Pseudopalisading necrosis Microvascular proliferation
IDH1 gene mutation First genetic alteration involved in gliomagenesis Located on 2q33 chromosome Tumor suppressor gene Mutations affect in most cases the arginine in position 132 of the amino acid sequence Mutated in : 82% of secondary GB 88% of low-grade astrocytomas 79% of oligodendrogliomas 5% of primary GB Christensen BC et al. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J Natl Cancer Inst. 2011 Jan 19;103(2):143-53
IDH 2 gene mutation Located on chromosome 15q26 Rare : <5% of diffuse gliomas More often detected in oligodendrogliomas than in astrocytomas IDH1/2 mutations = premalignant cells Early stage of oncogenesis (before p53/ 1p19q) Role in tumor progression is probably minor
TP53 mutation Leads to diffuse astrocytoma Tumor suppressor gene: delays entry into S phase so allows cells to correct DNA replication errors or enter apoptosis P16, Rb and CDK4 mutation Role in the transition from G1 to S (cell cycle) Half of anaplastic astrocytomas and nearly all GBs exhibit inactivation of this checkpoint. In astrocytomas, one of the most frequent mechanisms of cancelling this control is through p16 inactivation (homozygous deletion ++)
9p loss and 19q loss anaplastic astrocytomas 10q loss secondary GBM Other mutations: Chromosome 7 or 7q gain EGFR amplification
Grade II round nuclei and perinuclear halos perineuronal satellitosis calcifications low proliferation no microvascular proliferation no necrosis Grade III (Anaplastic O.) nuclear atypia high cellularity and mitotic figures branching capillaries microvascular proliferation foci of necrosis
IDH1/IDH2 1p/19q codeletion 80% of oligodendrogliomas 10% of diffuse astrocytomas Good prognosis with an overall survival time longer than 15 years p16 deletion uncommon: 15% of anaplastic oligodendrogliomas prognosis shorter overall survival
Two cell components are resembling astrocytoma and oligodendroglioma : usually intermingled (rare biphasic tumor) WHO grade II oligoastrocytoma: moderate cellularity low mitotic activity calcifications may be present WHO grade III Anaplastic oligoastrocytomas: high cellularity mitotic activity cellular pleomorphism microvascular proliferation necrosis -->GB (WHO grade IV)
30-70% LOH 1p and LOH 19q 30% mutations TP53 gene or LOH 17p Next edition of the WHO classification of nervous system: NO mixed gliomas astrocytomas or oligodendrogliomas based on the genetic alterations http://trialx.com/curebyte/2011/07/09/pictures-for-oligo-astrocytoma/
Therapy Current therapy Limited efficacy New molecular therapies GBs display defined molecular alterations, which make it suitable for targeted molecular therapies
IDH1-R132H mutant protein - potential target for immunotherapy IDH1 R132H mutant enzyme inhibitor- AGI- 5198 tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells Spontaneous TH1 and humoral IDH1(R132H)-specific responses are detected in IDH1(R132H) glioma patients IDH1(R132H) peptide vaccination induces TH1 and humoral responses in mice and reduces tumor growth Blocks the production of 2- hydroxyglutarate Induces histone demethylation Tumour growth was inhibited, the drug was well tolerated without signs of toxicity
Tumor volumes of TS603 xenografts in mice treated with vehicle, 150 mg/kg AGI-5198, or 450 mg/kg AGI-5198 (*P < 0.05, two-tailed test); n = 10 mice per cohort. Error bars, mean ± SEM. Growth of tumor (IDH1(R132H)1 or wild-type IDH11) after preventive vaccinationwith IDH1(R132H) (red) or vehicle (black)
EGFR targeted therapy A better tumor growth control might be achieved Cancer cell-egfr-membrane TK Gefitinib Erlotinib Nimotuzumab TP53 targeted therapy Virus internalized in the tumor cell nucleus: replicates here -> cell lysis - >infect other cells Onyx - 015 Cell adhesion nucleus Apoptosis Cell proliferation
Gliomas highly malignant tumors Poor rate survival Different morphological features different genetic alterations different malignancy The specifics mutations target therapy
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007). WHO classification of tumours of the central nervous system. IARC. Lyon, 2007 http://www.pubcan.org/cancer/4967/anaplastic-astrocytoma/histopathology Molecular diagnostics of gliomas: state of the art. Markus J. Riemenschneider Judith W. M. Jeuken Pieter Wesseling Guido Reifenberger. Acta Neuropathol. 2010 Nov;120(5):567-84 http://trialx.com/curebyte/2011/07/09/pictures-for-oligo-astrocytoma Olli Tynninen: Progression of diffuse gliomas; from the first diagnosis to the recurrence. academic dissertation; Department of Pathology Haartman Institute University of Helsinki and Helsinki University Central Hospital Brenda Auffinger et all, Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice, Front. Oncol., 25 February 2013, Review Articlehttp://www.sciencemag.org/content/340/6132/626/F4.expansion.html http://www.oncopathlabs.com/services/case-studies/newly-diagnosedoligodendroglioma Christensen et al.dna methylation, isocitrate dehydrogenase mutation, and survival in glioma. J Natl Cancer Inst. 2011 Jan 19;103(2):143-53 http://www.neurology.org/content/72/2/156/f1.expansion.html