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Could p53 and RAS alterations be responsible for the progression of cerebellar glioblastomas?

Vedrana P Milinkovic, University of Belgrade Institute for Biological Research Sinisa Stankovic; Milica K. Skender Gazibara, University of Belgrade School of Medicine Institute of Pathology; Emilija M. Manojlovic Gacic, University of Belgrade School of Medicine Institute of Pathology; Tatjana M. Gazibara, University of Belgrade School of Medicine Institute of Epidemiology; Nasta Tanic, Institute Vinca; Nikola T. Tanic, University of Belgrade Institute for Biological Research Sinisa Stankovic


Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor in adults. Majority of GBMs develop de novo (primary GBM) without evidence of a less malignant precursor lesion, while others, progressing from low-grade diffuse astrocytoma or anaplastic astrocytoma represent secondary GBM. GBM is most often located in the cerebral hemispheres, cerebellar localization is rare, reported only in 0.4–3.4% cases. Due to low incidence cerebellar GBMs (cGBM) are inadequately characterized. Inactivation of p53 tumor suppressor is an early and frequent event in GBM formation. Mutational activation of RAS proto-oncogenes is often present in various human tumors. All 5 cases of cGBM with matching recurrent tumors, operated from 2000 to 2012 in Belgrade, Serbia were analyzed in this study. All tumors showed moderate to intensive GFAP, Vimentin and S-100 immunopositivity, and were negative on CK and Synaptophysin.
Ki-67 % ranged from 0.3 to 41.61, and p53% 1.71 to 59.1. P53 mutations were detected in 5 samples, all with higher percentage of p53 positive nuclei. All enrolled patients had alterations in KRAS or HRAS gene, but identified mutations were not previously reported. Median survival of cGBM patients was 33.2 months, significantly longer compared to sGBM. This is the first report analyzing specific genetic alterations in cGBM. We postulate that p53 mutations might be responsible for the progression of cGBM. Premature STOP codon inductions, together with novel alterations in in RAS genes, suggest that RAS signaling is impaired and specific for cGBM. High incidence of RAS mutations, as well as significantly longer survival suggests that cGBM may have different mechanism of occurrence and progression in comparison with sGBM.

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