Fischer Ulrike, Keller Andreas, Leidinger Petra, Deutscher Stephanie, Heisel Sabrina, Urbschat Steffi, Lenhof Hans-Peter, Meese Eckart
Department of Human Genetics, Saarland University, 66421 Homburg/Saar, Germany.
Mol Cancer Res. 2008 Apr;6(4):576-84. doi: 10.1158/1541-7786.MCR-07-0283.
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.
为了进一步了解扩增在胶质瘤发生和复发中的生物学意义，我们对低级别胶质瘤中的扩增子频率和大小以及复发性胶质母细胞瘤体内的扩增子稳定性进行了表征。我们开发了一种12q13 - 21扩增子特异性基因组微阵列和一种生物信息学扩增预测工具，以分析40个胶质瘤样本中的扩增子频率、大小和维持情况，这些样本包括16个胶质母细胞瘤、10个间变性星形细胞瘤、7个WHO 2级星形细胞瘤和7个毛细胞型星形细胞瘤。尽管先前的研究报告了两个扩增子区域，但我们发现情况更为复杂，存在许多扩增子区域。分析这40个胶质瘤，我们发现所有分析的胶质母细胞瘤以及大多数毛细胞型星形细胞瘤、2级星形细胞瘤和间变性星形细胞瘤都显示出至少一个扩增子区域，这表明扩增频率比先前报道的要高得多。低级别胶质瘤中的扩增在大小上较小，并且与胶质母细胞瘤中的扩增显示出明显不同的分布模式。一个胶质母细胞瘤及其复发肿瘤显示出一个5 Mb的扩增子区域，该区域在6年内保持稳定。对扩增区域的表达分析揭示了10个过表达基因（即KUB3、CTDSP2、CDK4、OS - 9、DCTN2、RAB3IP、FRS2、GAS41、MDM2和RAP1B），这些基因在所有携带该扩增的病例中均持续过表达。我们的数据表明，12q13 - 21上的扩增（a）比先前认为的更频繁，且存在于低级别肿瘤中；（b）作为扩展区域长时间维持。
