Allelic gain and amplification on the long arm of chromosome 17 in anaplastic meningiomas.

Using comparative genomic hybridization (CGH) we have previously identified amplification at 17q21-qter as a common aberration in anaplastic meningiomas but not in atypical or benign meningiomas (19). To define the amplified genomic region, we analyzed 44 meningeal tumors, including 7 benign meningiomas of World Health Organization (WHO) grade 1,19 atypical meningiomas (WHO grade II) and 18 anaplastic meningiomas (WHO grade III) at 46 chromosome 17 loci (including 42 17q loci). In line with the CGH data we found evidence of increased numbers of alleles on 17q. The incidence rose with malignancy grade, culminating at 61% (11 of 18 cases) in the anaplastic meningioma group. The majority of cases showing increased allele numbers had, on average, low-level allelic gains (relative increase in allele dosage of 2- to 5-fold). Amplification of alleles (defined here as an average relative increase in allele dosage of more than 5 times) was detected in 2 anaplastic meningiomas. The amplification patterns in these tumors defined a number of common regions of amplification/increased allele copy number, the best defined include one between D17S790 and D17S1607 and one between D17S1160 and PS6K. Real-time PCR analysis of the PS6K candidate gene revealed no high-level amplification despite this affecting adjacent loci. Our findings are fundamental for the identification of the gene(s) in 17q22-q23 that is (are) the target(s) for increased copy number in anaplastic meningiomas and possibly other tumor types.

Comprehensive analysis of genomic alterations in gliosarcoma and its two tissue components.

Gliosarcoma is a variant of glioblastoma multiforme characterized by two components displaying gliomatous or sarcomatous differentiation. We investigated 38 gliosarcomas for aberrations of tumor-suppressor genes and proto-oncogenes that are commonly altered in glioblastomas. Amplification of CDK4, MDM2, EGFR, and PDGFRA were found in 11% (4/35), 8% (3/38), 8% (3/38), and 3% (1/35) of the tumors, respectively. Nine of 38 gliosarcomas (24%) carried TP53 mutations. PTEN mutations were identified in 45% (9/20) of the investigated tumors. Twenty gliosarcomas were analyzed by comparative genomic hybridization (CGH). Chromosomal imbalances commonly detected were gains on chromosomes 7 (15/20; 75%), X (4/20; 20%), 9q, and 20q (3/20, 15% each); and losses on chromosomes 10 and 9p (7/20, 35% each), and 13q (3/20, 15%). Five different high-level amplifications were mapped to 4q12-q21 (1 case), 6p21 (1 case), 7p12 (2 cases), proximal 12q (4 cases), and 14q32 (1 case) by CGH. Southern blot and/or differential PCR analyses identified amplification of PDGFRA (4q12), CCND3 (6p21), EGFR (7p12), CDK4 (12q14) and/or MDM2 (12q14.3-q15), and AKT1 (14q32.3) in the respective tumors. Separate analysis of the gliomatous and sarcomatous components of eight gliosarcomas by CGH after microdissection and universal DNA amplification revealed that both components shared 57% of the chromosomal imbalances detected. Taken together, our data indicate that the genomic changes in gliosarcomas closely resemble those found in glioblastomas. However, the number of chromosomes involved in imbalances in gliosarcomas was significantly lower than that in glioblastomas, indicating a higher genomic stability in gliosarcomas. In addition, we provide further support for the hypothesis that the gliomatous and sarcomatous components are derived from a single precursor cell clone, which progressed into subclones with distinct morphological features during tumor evolution. According to our data, gain/amplification of genes on proximal 12q may facilitate the development of a sarcomatous phenotype.