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Glioblastoma may develop rapidly without evidence for precursor lesions (primary glioblastomas), or progress from diffuse or anaplastic astrocytomas (secondary glioblastomas). Despite having distinct genetic profiles, these glioblastoma subtypes have similar histological features. We hypothesized that the highly malignant phenotype of glioblastoma may be attributable to genetic alterations that are common to both glioblastoma subtypes. In the present study, we first searched for commonly (>35%) amplified genes in glioblastomas with IDH1 mutation (a hallmark of secondary glioblastoma) and those without IDH1 mutation (typical for primary glioblastoma) in data from The Cancer Genome Atlas ( TCGA). A total of 25 genes were identified, of which 21 were located at 7q31-34. We then screened 264 gliomas (70 glioblastomas, 112 diffuse astrocytomas, 82 oligodendrogliomas) for gain of the MET at 7q31.2 with quantitative polymerase chain reaction ( PCR). MET gain was detected in primary glioblastomas (47%) and secondary glioblastomas (44%), suggesting that this genetic alteration plays a role in the pathogenesis of both glioblastoma subtypes. MET gain was also common in diffuse astrocytomas (38%), but less frequent in oligodendrogliomas (16%). MET gain in diffuse astrocytomas was associated with shorter survival (median, 43.0 vs. 70.7 months; P = 0.004), suggesting that MET gain is a useful prognostic marker for diffuse astrocytomas. [ABSTRACT FROM AUTHOR]

We recently reported that the vast majority (>90%) of low-grade diffuse gliomas (diffuse astrocytoma, oligoastrocytoma and oligodendroglioma) carry at least one of the following genetic alterations: IDH1/2 mutation, TP53 mutation or 1p/19q loss. Only 7% of cases were triple-negative (ie, lacking any of these alterations). In the present study, array comparative genomic hybridization (CGH) in 15 triple-negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 ( p14ARF, p15INK4b, p16INK4a loci) and 13q14-13q32 (containing the RB1 locus) in three and two cases, respectively. Further analyses in 31 triple-negative cases as well as a total of 160 non-triple-negative cases revealed that alterations in the RB1 pathway (homozygous deletion and promoter methylation of the p15INK4b, p16INK4a and RB1 genes) were significantly more frequent in triple-negative (26%) than in non-triple-negative cases (11%; P = 0.0371). Multivariate analysis after adjustment for age, histology and treatment showed that RB1 pathway alterations were significantly associated with unfavorable outcome for patients with low-grade diffuse glioma [hazard ratio, 3.024 (1.279-6.631); P = 0.0057]. These results suggest that a fraction of low-grade diffuse gliomas lacking common genetic alterations may develop through a distinct genetic pathway, which may include loss of cell-cycle control regulated by the RB1 pathway. [ABSTRACT FROM AUTHOR]