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Abstracts iii22NEURO-ONCOLOGY • MAY 2017 63-76) in non-codeleted OG. Mixed histology was not significant (HR 1.49, 95%CI; p=0.11 BACKGROUND: Although major advances have been accomplished over the last years in their characterization, 1p/19q-codeleted anaplastic gliomas have variable clinical behavior and mysterious 1p/19q-codeletion "driven" molecular oncogenesis. We have recently shown that the most common alteration (i.e. 9p21.3 allelic loss detected in 42% of cases) is an independent prognostic factor in this tumor type. However, less frequent Genomic Copy Number Variations (CNV) may also have clinical value and may shed light on molecular oncogenesis of this tumor type. METHODS: A cohort of 197, 1p/19q-codeleted grade III gliomas was collected as part of the French POLA network. Clinical, pathological and molecular information were recorded and the patients were clinically followed up. CNV analysis was performed using SNP arrays. Computational biology and machine learning analysis were applied to identify less common additional CNV events associated with overall survival and other clinical-pathological variables RESULTS: Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. 46 focal amplification events and 22 focal deletion events were identified. 12 of the focal events overlapped with known cancer related genomic regions. 24 focal CNV areas were associated with survival and five of them were significantly associated with survival after multivariate analysis. 9/24 signals, detected in 3 to 26 percent of patients, were validated using an external cohort of gliomas of the Cancer Genome Atlas. Five of the validated signals contain a cancer related gene or MIR: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozigosity, FGFR3 amplification, and ARNT amplification. The CNV profile enables better survival prediction compared to clinical risk assessment. CONCLUSIONS: Several recurrent CNV events are characteristics for 1p/19q-codeleted grade III gliomas. These genomic regions are associated with survival and enable better survival prediction. More important, they may help identifying potential genes for understanding oncogenesis and for personalized therapy.

The increase in p-Akt staining within these PTEN-deficient gliomas is consistent with what would be predicted from unchecked PI 3-K signaling. Furthermore, the immunohistochemically detected colocalization of p-Akt and MMP-2 and MMP-9 supports the authors' in vitro studies and the proposed linkage between PI 3-K signaling and MMP activity in gliomas.

Glioblastomas often show activation of epidermal growth factor receptor (EGFR) and loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor, but it is not known if these two genetic lesions act together to transform cells. To answer this question, we infected PTEN-/- neural precursor cells with a retrovirus encoding EGFRvIII, which is a constitutively activated receptor. EGFRvIII PTEN-/- cells formed highly mitotic tumors with nuclear pleomorphism, necrotic areas, and glioblastoma markers. The transformed cells showed increased cell proliferation, centrosome amplification, colony formation in soft agar, self-renewal, expression of the stem cell marker CD133, and resistance to oxidative stress and ionizing radiation. The RAS/mitogen-activated protein kinase (ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways were activated, and checkpoint kinase 1 (Chk1), the DNA damage regulator, was phosphorylated at S280 by Akt, suppressing Chk1 phosphorylation at S345 in response to ionizing irradiation. The PTEN-/- cells showed low levels of DNA damage in the absence of irradiation, which was increased by EGFRvIII expression. Finally, secondary changes occurred during tumor growth in mice. Cells from these tumors showed decreased tumor latencies and additional chromosomal aberrations. Most of these tumor lines showed translocations of mouse chromosome 15. Intracranial injections of one of these lines led to invasive, glial fibrillary acidic protein-positive, nestin-positive tumors. These results provide a molecular basis for the occurrence of these two genetic lesions in brain tumors and point to a role in induction of genomic instability.