Dehan E, Ben-Dor A, Liao W, Lipson D, Frimer H, Rienstein S, Simansky D, Krupsky M, Yaron P, Friedman E, Rechavi G, Perlman M, Aviram-Goldring A, Izraeli S, Bittner M, Yakhini Z, Kaminski N
Sackler School of Medicine, Tel-Aviv University, Israel.
Lung Cancer. 2007 May;56(2):175-84. doi: 10.1016/j.lungcan.2006.12.010. Epub 2007 Jan 25.
Alterations in genomic content and changes in gene expression levels are central characteristics of tumors and pivotal to the tumorigenic process. We analyzed 23 non-small cell lung cancer (NSCLC) tumors by array comparative genomic hybridization (array CGH). Aberrant regions identified included well-characterized chromosomal aberrations such as amplifications of 3q and 8q and deletions of 3p21.31. Less frequently identified aberrations such as amplifications of 7q22.3-31.31 and 12p11.23-13.2, and previously unidentified aberrations such as deletion of 11q12.3-13.3 were also detected. To enhance our ability to identify key acting genes residing in these regions, we combined array CGH results with gene expression profiling performed on the same tumor samples. We identified a set of genes with concordant changes in DNA copy number and expression levels, i.e. overexpressed genes located in amplified regions and underexpressed genes located in deleted regions. This set included members of the Wnt/beta-catenin pathway, genes involved in DNA replication, and matrix metalloproteases (MMPs). Functional enrichment analysis of the genes both overexpressed and amplified revealed a significant enrichment for DNA replication and repair, and extracellular matrix component gene ontology annotations. We verified the changes in expressions of MCM2, MCM6, RUVBL1, MMP1, MMP12 by real-time quantitative PCR. Our results provide a high resolution map of copy number changes in non-small cell lung cancer. The joint analysis of array CGH and gene expression analysis highlights genes with concordant changes in expression and copy number that may be critical to lung cancer development and progression.
基因组含量的改变和基因表达水平的变化是肿瘤的核心特征，也是肿瘤发生过程的关键因素。我们通过阵列比较基因组杂交（阵列CGH）分析了23例非小细胞肺癌（NSCLC）肿瘤。鉴定出的异常区域包括特征明确的染色体畸变，如3q和8q的扩增以及3p21.31的缺失。还检测到频率较低的异常，如7q22.3 - 31.31和12p11.23 - 13.2的扩增，以及之前未鉴定出的异常，如11q12.3 - 13.3的缺失。为了增强我们识别位于这些区域的关键作用基因的能力，我们将阵列CGH结果与对相同肿瘤样本进行的基因表达谱分析相结合。我们鉴定出一组在DNA拷贝数和表达水平上具有一致变化的基因，即位于扩增区域的过表达基因和位于缺失区域的低表达基因。这一组包括Wnt/β - 连环蛋白通路成员、参与DNA复制的基因以及基质金属蛋白酶（MMPs）。对过表达和扩增基因的功能富集分析显示，DNA复制和修复以及细胞外基质成分基因本体注释显著富集。我们通过实时定量PCR验证了MCM2、MCM6、RUVBL1、MMP1、MMP12的表达变化。我们的结果提供了非小细胞肺癌拷贝数变化的高分辨率图谱。阵列CGH和基因表达分析的联合分析突出了在表达和拷贝数上具有一致变化的基因，这些基因可能对肺癌的发生和发展至关重要。
