Nikolsky Yuri, Sviridov Evgeny, Yao Jun, Dosymbekov Damir, Ustyansky Vadim, Kaznacheev Valery, Dezso Zoltan, Mulvey Laura, Macconaill Laura E, Winckler Wendy, Serebryiskaya Tatiana, Nikolskaya Tatiana, Polyak Kornelia
GeneGo, Inc., St. Joseph, Michigan, USA.
Cancer Res. 2008 Nov 15;68(22):9532-40. doi: 10.1158/0008-5472.CAN-08-3082.
A single cancer cell contains large numbers of genetic alterations that in combination create the malignant phenotype. However, whether amplified and mutated genes form functional and physical interaction networks that could explain the selection for cells with combined alterations is unknown. To investigate this issue, we characterized copy number alterations in 191 breast tumors using dense single nucleotide polymorphism arrays and identified 1,747 genes with copy number gain organized into 30 amplicons. Amplicons were distributed unequally throughout the genome. Each amplicon had distinct enrichment pattern in pathways, networks, and molecular functions, but genes within individual amplicons did not form coherent functional units. Genes in amplicons included all major tumorigenic pathways and were highly enriched in breast cancer-causative genes. In contrast, 1,188 genes with somatic mutations in breast cancer were distributed randomly over the genome, did not represent a functionally cohesive gene set, and were relatively less enriched in breast cancer marker genes. Mutated and gained genes did not show statistically significant overlap but were highly synergistic in populating key tumorigenic pathways including transforming growth factor beta, WNT, fibroblast growth factor, and PIP3 signaling. In general, mutated genes were more frequently upstream of gained genes in transcription regulation signaling than vice versa, suggesting that mutated genes are mainly regulators, whereas gained genes are mostly regulated. ESR1 was the major transcription factor regulating amplified but not mutated genes. Our results support the hypothesis that multiple genetic events, including copy number gains and somatic mutations, are necessary for establishing the malignant cell phenotype.
单个癌细胞包含大量的基因改变，这些改变共同造就了恶性表型。然而，扩增和突变的基因是否形成功能和物理相互作用网络，从而解释对具有联合改变的细胞的选择，目前尚不清楚。为了研究这个问题，我们使用高密度单核苷酸多态性阵列对191例乳腺肿瘤中的拷贝数改变进行了表征，并鉴定出1747个拷贝数增加的基因，这些基因被组织成30个扩增子。扩增子在整个基因组中分布不均。每个扩增子在通路、网络和分子功能方面具有独特的富集模式，但单个扩增子内的基因并未形成连贯的功能单元。扩增子中的基因包括所有主要的致瘤通路，并且在乳腺癌致病基因中高度富集。相比之下，乳腺癌中1188个发生体细胞突变的基因在基因组中随机分布，不代表一个功能上有凝聚力的基因集，并且在乳腺癌标记基因中的富集程度相对较低。突变和扩增的基因没有显示出统计学上的显著重叠，但在填充关键的致瘤通路（包括转化生长因子β、WNT、成纤维细胞生长因子和PIP3信号通路）方面具有高度协同作用。一般来说，在转录调控信号中，突变基因比扩增基因更频繁地位于上游，这表明突变基因主要是调节因子，而扩增基因大多是被调节的。ESR1是调节扩增但未突变基因的主要转录因子。我们的结果支持这样的假设，即包括拷贝数增加和体细胞突变在内的多种遗传事件对于建立恶性细胞表型是必要的。
