Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
PLoS One. 2011 Jan 31;6(1):e14632. doi: 10.1371/journal.pone.0014632.
Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification.
20q 染色体臂的重复发生在前列腺癌、宫颈癌、结肠癌、胃癌、膀胱癌、黑色素瘤、胰腺癌和乳腺癌中，表明 20q 扩增可能在肿瘤发生中起因果作用。根据另一种观点，染色体失衡主要是癌症进展的常见副作用。为了测试特定的基因组异常是否可能作为癌症起始事件，我们建立了一种体外系统，该系统模拟了前列腺肿瘤形成早期阶段的进化过程；通过过表达人端粒酶催化亚单位 hTERT 使正常前列腺细胞永生化，并培养 650 天，直到观察到几个转化标志。在不同时间测量基因表达模式并通过光谱核型分析监测染色体异常。在该过程的早期发生了几种染色体异常，特别是 20q 染色体臂的重复，并且在细胞群体中固定下来，而其他异常在出现后不久就消失了。广泛的生物信息学工具，应用于我们的数据和来自几个癌症数据库的数据，揭示了自发的 20q 扩增可以促进癌症的发生。我们的计算模型表明，20q 扩增诱导了几个特定的癌症相关途径的失调，包括 MAPK 途径、p53 途径和 Polycomb 组因子。此外，鉴定出 Myc、AML、B-连环蛋白和 ETS 家族转录因子的激活是由 20q 扩增驱动的癌症发展的重要步骤。最后，我们确定了 13 个“癌症起始基因”，位于 20q13 上，这些基因在许多肿瘤中显著过表达，表达水平与肿瘤分级和预后相关，表明这些基因在 20q 扩增后诱导了恶性过程。
