Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma
Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma
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DOI：
10.1073/pnas.0710052104
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发表时间：
2007-12-11
影响因子：
11.1
通讯作者：
Sellers, William R.
中科院分区：
文献类型：
--
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
对癌症基因组改变的全面了解是诊断学、免疫学和靶向治疗的关键基础。系统性的癌症基因组分析工作正在进行中，但由于缺乏一个统计框架来区分有意义的事件和随机的背景畸变，这一分析受到了阻碍。在这里，我们描述了一种系统的方法，称为基因组识别的重要目标在癌症（GISTIC），旨在分析染色体畸变的癌症。我们用它来研究141例胶质瘤的染色体畸变，并将结果与两项先前的研究进行比较。传统方法突出了数百个改变的区域，研究之间几乎没有一致性。新的方法揭示了一个高度一致的图片，涉及约35个重大事件，包括16-18个广泛的染色体臂大小附近的事件和16-21个焦点事件。这些事件中大约有一半对应于已知的癌症相关基因，其中只有一些先前与胶质瘤有关。我们还表明，叠加广泛和焦点事件可能有不同的生物后果。具体而言，7号染色体广泛扩增的胶质瘤具有与重叠局灶性EGFR扩增的胶质瘤不同的性质：广泛事件部分通过对MET及其配体HGF的影响起作用，并与体外MET依赖性相关。我们的研究结果支持癌症基因组的系统表征的可行性和实用性。
Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximate to 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focal EGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.