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.

Biopsies routinely performed for the histopathological diagnosis of oral epithelial lesions before treatment were screened for chromosomal imbalances by comparative genomic hybridization. Comparative genomic hybridization was performed on 12 oral premalignant lesions (OPLs; dysplasias and carcinomas in situ) and 14 oral squamous cell carcinomas (OSCCs). Eight biopsies displayed areas of different histopathological appearance , so that OPLs and OSCCs from the same patient were analyzed. To avoid contamination with nonneoplastic cells , defined cell populations were isolated by micromanipulation with a glass needle. Before comparative genomic hybridization analysis , universal DNA amplification was performed using the DOP-polymerase chain reaction protocol. In the 14 OSCCs examined , the average number of chromosomal imbalances was significantly higher than in the 12 OPLs (mean ؎ SEM: 11.9 ؎ 1.9 versus 3.2 ؎ 1.2; P ‫؍‬ 0.003). The DNA copy number changes identified in more than one OPL were gains on 8q ( Oral and oropharyngeal squamous cell carcinoma is the sixth most frequently occurring cancer worldwide, with approximately 400,000 new cases diagnosed each year.1 A high incidence of second primary lesions, both malignant and premalignant, was observed in patients with oral squamous cell carcinoma (OSCC), leading to the concept of field cancerization.2 This phenomenon is partly attributed to the fact that the entire oral mucosa is exposed to exogenous cancer-promoting substances such as alcohol and tobacco. Some OSCCs are preceded by oral premalignant lesions (OPLs), which include dysplasias and carcinomas in situ (CIS) of the oral mucosa. However, 64% of OPLs do not progress to malignancy. 3In most studies on the genetic alterations in cancer of the upper aerodigestive tract, OSCCs are included in the more heterogeneous group of squamous cell carcinomas (SCCs) of the head and neck (HNSCCs). In HNSCCs, losses of genomic material were identified on 3p, 5q, 7q, 8p, 9p, 11q, 13q, 17p, and 18q by chromosome banding Supported by the Deutsche Krebshilfe (grants 10-1124-Li1 and 10-0976-Re1).

Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent patients (nineteen B‐cell lymphomas and one T‐cell lymphoma) were investigated for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%) hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL without homozygous CDKN2A loss revealed methylation of the CpG island within exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either completely negative or showed expression restricted to single tumor cells. None of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1 revealed no amplification, rearrangement or overexpression. The retinoblastoma protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG: Arg to Trp). No evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl‐2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous deletion or DNA methylation represents an important molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated appear to be of minor significance in these tumors.