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Cancer Genes and Genomics

A Different View on DNA Amplifications Indicates Frequent, Highly Complex, and Stable Amplicons on 12q13-21 in Glioma

Departments of ¹ Human Genetics and ² Neurosurgery, Saarland University, Homburg/Saar, Germany and ³ Center for Bioinformatics, Saarland University, Saarbrücken, Germany

Requests for reprints: Ulrike Fischer, Department of Human Genetics, Saarland University, Building 60, 66421 Homburg/Saar, Germany. Phone: 49-6841-1626289; Fax: 49-6841-1626186. E-mail: hgufis{at}uniklinik-saarland.de

To further understand the biological significance of amplifications for glioma development and recurrencies, we characterized amplicon frequency and size in low-grade glioma and amplicon stability in vivo in recurring glioblastoma. We developed a 12q13-21 amplicon–specific genomic microarray and a bioinformatics amplification prediction tool to analyze amplicon frequency, size, and maintenance in 40 glioma samples including 16 glioblastoma, 10 anaplastic astrocytoma, 7 astrocytoma WHO grade 2, and 7 pilocytic astrocytoma. Whereas previous studies reported two amplified subregions, we found a more complex situation with many amplified subregions. Analyzing 40 glioma, we found that all analyzed glioblastoma and the majority of pilocytic astrocytoma, grade 2 astrocytoma, and anaplastic astrocytoma showed at least one amplified subregion, indicating a much higher amplification frequency than previously suggested. Amplifications in low-grade glioma were smaller in size and displayed clearly different distribution patterns than amplifications in glioblastoma. One glioblastoma and its recurrencies revealed an amplified subregion of 5 Mb that was stable for 6 years. Expression analysis of the amplified region revealed 10 overexpressed genes (i.e., KUB3, CTDSP2, CDK4, OS-9, DCTN2, RAB3IP, FRS2, GAS41, MDM2, and RAP1B) that were consistently overexpressed in all cases that carried this amplification. Our data indicate that amplifications on 12q13-21 (a) are more frequent than previously thought and present in low-grade tumors and (b) are maintained as extended regions over long periods of time. (Mol Cancer Res 2008;6(4):576–84)