Unger K, Malisch E, Thomas G, Braselmann H, Walch A, Jackl G, Lewis P, Lengfelder E, Bogdanova T, Wienberg J, Zitzelsberger H
Institut für Molekulare Strahlenbiologie, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH, Germany.
Oncogene. 2008 Jul 31;27(33):4592-602. doi: 10.1038/onc.2008.99. Epub 2008 Apr 14.
The aim of this study is to investigate additional genetic alterations in papillary thyroid carcinomas (PTCs) with known RET/PTC rearrangements. We applied array-based comparative genomic hybridization (array CGH) to 33 PTC (20 PTC from adults, 13 post-Chernobyl PTC from children) with known RET/PTC status. Principal component analysis and hierarchical cluster analysis identified cases with similar aberration patterns. Significant deviations between tumour-groups were obtained by statistical testing (Fisher's exact test in combination with Benjamini-Hochberg FDR-controlling procedure). FISH analysis on FFPE sections was applied to validate the array CGH data. Deletions were found more frequently in RET/PTC-positive and RET/PTC-negative tumours than amplifications. Specific aberration signatures were identified that discriminated between RET/PTC-positive and RET/PTC-negative cases (aberrations on chromosomes 1p, 3q, 4p, 7p, 9p/q, 10q, 12q, 13q and 21q). In addition, childhood and adult RET/PTC-positive cases differ significantly for a deletion on the distal part of chromosome 1p. There are additional alterations in RET/PTC-positive tumours, which may act as modifiers of RET activation. In contrast, alterations in RET/PTC-negative tumours indicate alternative routes of tumour development. The data presented serve as a starting point for further studies on gene expression and function of genes identified in this study.
本研究的目的是调查已知存在RET/PTC重排的甲状腺乳头状癌（PTC）中的其他基因改变。我们对33例已知RET/PTC状态的PTC（20例成人PTC，13例切尔诺贝利事故后儿童PTC）应用了基于芯片的比较基因组杂交（芯片CGH）技术。主成分分析和层次聚类分析确定了具有相似畸变模式的病例。通过统计检验（Fisher精确检验结合Benjamini-Hochberg FDR控制程序）获得肿瘤组之间的显著差异。对福尔马林固定石蜡包埋（FFPE）切片进行荧光原位杂交（FISH）分析以验证芯片CGH数据。在RET/PTC阳性和RET/PTC阴性肿瘤中，缺失比扩增更常见。识别出了区分RET/PTC阳性和RET/PTC阴性病例的特定畸变特征（1号染色体短臂、3号染色体长臂、4号染色体短臂、7号染色体短臂、9号染色体短臂/长臂、10号染色体长臂、12号染色体长臂、13号染色体长臂和21号染色体长臂上的畸变）。此外，儿童和成人RET/PTC阳性病例在1号染色体短臂远端的缺失方面存在显著差异。RET/PTC阳性肿瘤中存在其他改变，这些改变可能作为RET激活的调节因子。相比之下，RET/PTC阴性肿瘤中的改变表明肿瘤发展的替代途径。所呈现的数据为进一步研究本研究中鉴定的基因的表达和功能提供了一个起点。
