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Refined Mapping of 12q13–q15 Amplicons in Human Malignant Gliomas Suggests CDK4/SAS and MDM2 as Independent Amplification Targets¹

Department of Neuropathology and Center for Biological and Medical Research [G. R.] and Department of Dermatology [J. R.], Heinrich Heine University, Moorenstrasse 5, D-40225 Düsseldorf, Germany; Ludwig Institute for Cancer Research, Stockholm Branch, and Institute for Oncology and Pathology, Division of Tumor Pathology, Konung Gustay V Research Institute, Karolinska Hospital, S-17176 Stockholm, Sweden [K. I., V. P. C.]; and Laboratory of Cancer Genetics, National Center for Human Genome Research, NIH, Bethesda, Maryland 20892 [A. G. E., P. S. M.]

We have reported previously that about 15% of anaplastic astrocytomas and glioblastomas show amplification and overexpression of one or more genes from chromosomal segment 12q13–q15 (G. Reifenberger et al., Cancer Res., 54, 4299–4303, 1994). The genes most frequently amplified and overexpressed were CDK4 (with coamplification of SAS) and MDM2. Because individual malignant gliomas showed CDK4/SAS amplification but no MDM2 amplification and vice versa, the possibility remained of a common amplification target gene located between CDK4 and MDM2. We have addressed this question by performing a detailed amplicon mapping of a series of 24 primary malignant gliomas and two glioblastoma cell lines with 12q13–q15 amplification. All tumors and cell lines were analyzed at eight gene loci and six anonymous loci from 12q13–q15, including seven loci located between CDK4 and MDM2. These studies revealed two centers of amplification, one at CDK4/SAS and the other at MDM2. A number of loci located close to either MDM2 or CDK4/SAS, including the genes GADD153, GLI, RAP1B, A2MR, and IFNG, were found to be coamplified in some tumors but not overexpressed consistently. All amplicons were discontinuous between CDK4/SAS and MDM2. Our results thus exclude a common amplification target between CDK4/SAS and MDM2 and provide additional evidence that these genes represent two independent targets of selection.

¹ Supported by grants from the Swedish Cancer Fund, the Konung Gustav V Forskning Fund, Stockholm Cancer Society, Knut and Alice Wallenberg Fund, Axel and Margret Ax: son Johnson Fund, Grant Re938/2-1 from the Deutsche Forschungsgemeinschaft, and Grant 10-0976-Re1 from the Deutsche Krebshilfe.

² These authors contributed equally to this work.

³ To whom requests for reprints should be addressed. Phone: 4687293830; Fax: 468323662.

Received 9/ 9/96. Accepted 10/ 2/96.

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