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Anghileri E.,Unit of Molecular Neuro oncology | Eoli M.,Unit of Molecular Neuro oncology | Paterra R.,Unit of Molecular Neuro oncology | Ferroli P.,Fondazione IRCCS C. Besta | And 7 more authors.
Journal of Neuro-Oncology | Year: 2012

Cerebellar liponeurocytoma (cLPN) is a very rare central nervous system (CNS) tumour recently recognized as a clinical and pathological entity distinct from medulloblastoma (MB), and included in the WHO classification of CNS tumours under the heading ''glioneuronal tumours''. cLPN typically develop in adult age and have a favourable prognosis compared with MB. In this work, we reviewed the clinical and neuroradiological data of two novel cases of adult cLPN diagnosed at our institution; one patient developed distant metastases. We tried to identify novel molecular markers for this malignancy. We found that the transcription factor NEUROG1 (but not ATOH1) is expressed in cLPN, unlike normal adult cerebellum, and that fatty acid binding protein 4 (FABP4), typically found in adipocytes, is significantly overexpressed compared with both normal adult cerebellum and human MB. These findings suggest cLPN occur as a result of transformation of cerebellar progenitors, which are distinct from cerebellar granule progenitors, and aberrantly differentiate into adipocyte-like tumour cells. They also suggest that analysis of FABP4 expression is of help to differentiate cLPN from MB. © 2012 Springer Science+Business Media, LLC.


Labussiere M.,Paris-Sorbonne University | Boisselier B.,Paris-Sorbonne University | Boisselier B.,Institute Du Cerveau Et Of La Moelle Epiniere Icm | Mokhtari K.,Paris-Sorbonne University | And 15 more authors.
Neurology | Year: 2014

Objective: To identify the prognostic significance of TERT promoter mutations (TERTp-mut) and their associations with common molecular alterations in glioblastomas (GBMs). Methods: We sequenced the TERTp-mut in DNA from 395 GBMs and analyzed the results with their respective histology, genetic profile (IDH1 mutation, EGFR amplification, CDKN2A homozygous deletion, loss of chromosome 10, TP53 mutation), and overall survival (OS). Results: TERTp-mut were found in 299 of 395 GBMs (75.7%) and were associated with an older age (median 59.6 years for TERTp-mut vs 53.6 years for TERT promoter wild type [TERTp-wt], p < 0.0001). TERTp-mut was an independent factor of poor prognosis (OS=13.8 vs 18.4 months), in both IDH-mutated (OS=13.8 vs 37.6 months, p=0.022) and IDH-wt GBMs (OS=13.7 vs 17.5 months, p=0.006). TERTp-mut was associated with IDH-wt, EGFR amplification, CDKN2A deletion, and chromosome 10q loss, but not with MGMT promoter methylation. In the TERTp-wt group, OS was twice longer in EGFR-wt than in EGFR amplification GBMs (OS=26.6 vs 13.3 months; p=0.005). In the EGFR-wt group, patients with TERTp-wt had a significantly better outcome (OS=26.3 vs 12.5 months, p < 0.0001), whereas in the EGFR amplification group, patients with TERTp-mut survived longer (OS=15.8 vs 13.3 months, p=0.05). Taken together, the absence of both EGFR amplification and TERTp-mut is associated with longer survival in patients with GBM (26.5 months for patients with IDH-wt, 36.7 months for patients with IDH mutation). Conclusions: The analysis of TERTp-mut, in combination with EGFR amplification and IDH mutation status, refines the prognostic classification of GBMs. © 2014 American Academy of Neurology.


Pessina S.,Unit of Molecular Neuro Oncology | Cantini G.,Unit of Molecular Neuro Oncology | Kapetis D.,Fondazione Irccs Instituto Neurologico C Besta | Cazzato E.,Unit of Molecular Neuro Oncology | And 3 more authors.
OncoImmunology | Year: 2016

Abcc3, a member of the ATP-binding cassette transporter superfamily, plays a role in multidrug resistance. Here, we found that Abcc3 is highly expressed in blood-derived NK cells but not in CD8+ T cells. In GL261 glioma-bearing mice treated with the alkylating agent temozolomide (TMZ) for 5 d, an early increased frequency of NK cells was observed. We also found that Abcc3 is strongly upregulated and functionally active in NK cells from mice treated with TMZ compared to controls. We demonstrate that Abcc3 is critical for NK cell survival during TMZ administration; more importantly, Akt, involved in lymphocyte survival, is phosphorylated only in NK cells expressing Abcc3. The resistance of NK cells to chemotherapy was accompanied by increased migration and homing in the brain at early time points. Cytotoxicity, evaluated by IFNγ production and specific lytic activity against GL261 cells, increased peripherally in the later phases, after conclusion of TMZ treatment. Intra-tumor increase of the NK effector subset as well as in IFNγ, granzymes and perforin-1 expression, were found early and persisted over time, correlating with a profound modulation on glioma microenvironment induced by TMZ. Our findings reveal an important involvement of Abcc3 in NK cell resistance to chemotherapy and have important clinical implications for patients treated with chemo-immunotherapy. © Sara Pessina, Gabriele Cantini, Dimos Kapetis, Emanuela Cazzato, Natalia Di Ianni, Gaetano Finocchiaro, and Serena Pellegatta.


PubMed | Unit of Molecular Neuro oncology
Type: Case Reports | Journal: Journal of neuro-oncology | Year: 2012

Cerebellar liponeurocytoma (cLPN) is a very rare central nervous system (CNS) tumour recently recognized as a clinical and pathological entity distinct from medulloblastoma (MB), and included in the WHO classification of CNS tumours under the heading glioneuronal tumours. cLPN typically develop in adult age and have a favourable prognosis compared with MB. In this work, we reviewed the clinical and neuroradiological data of two novel cases of adult cLPN diagnosed at our institution; one patient developed distant metastases. We tried to identify novel molecular markers for this malignancy. We found that the transcription factor NEUROG1 (but not ATOH1) is expressed in cLPN, unlike normal adult cerebellum, and that fatty acid binding protein 4 (FABP4), typically found in adipocytes, is significantly overexpressed compared with both normal adult cerebellum and human MB. These findings suggest cLPN occur as a result of transformation of cerebellar progenitors, which are distinct from cerebellar granule progenitors, and aberrantly differentiate into adipocyte-like tumour cells. They also suggest that analysis of FABP4 expression is of help to differentiate cLPN from MB.

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