Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cell. 2013 Nov 7;155(4):948-62. doi: 10.1016/j.cell.2013.10.011. Epub 2013 Oct 31.
Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.
非整倍性已被公认为癌症的一个标志 100 多年，然而，目前还没有出现一种能够解释癌症中非整倍性反复出现模式的一般理论。在这里，我们开发了肿瘤抑制因子和癌基因（TUSON）探索者，这是一种分析肿瘤中突变特征模式并预测任何单个基因作为肿瘤抑制因子（TSG）或癌基因（OG）的可能性的计算方法。通过分析 >8200 对肿瘤-正常样本，我们提供了统计证据，表明有更多的基因具有癌症驱动特性，形成了一个连续的致癌潜力。我们将驱动基因预测与体细胞拷贝数改变的信息相结合，发现染色体上 TSG（停止基因）、OG 和必需基因（GO 基因）的分布和活性可以预测癌症基因组中特有的非整倍性和拷贝数变异的复杂模式。我们提出，癌症基因组是通过累积的杂合不足和三倍体敏感性过程形成的。
