Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Nature. 2010 Feb 18;463(7283):893-8. doi: 10.1038/nature08768.
The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.
癌症基因组是由体细胞突变和选择这两个双重过程塑造的。在癌症基因组中，纯合缺失发生在隐性癌症基因上，这可能赋予了它们选择性生长优势，也发生在脆性位点上，这些脆性位点被认为反映了局部 DNA 断裂率的增加。然而，癌症基因组中的大多数纯合缺失仍然无法解释。在这里，我们在 746 个癌细胞系中鉴定了 2428 个体细胞纯合缺失。这些缺失覆盖了 11%的编码蛋白质的基因，因此，这些基因对于人类细胞的生存并不是必需的。我们推导出了结构特征，可以区分隐性癌症基因上的纯合缺失和脆性位点上的纯合缺失。将这些结构特征应用于未解释的纯合缺失簇表明，其中许多缺失发生在固有脆弱区域，而一小部分缺失则覆盖了隐性癌症基因。这些结果说明了如何使用结构特征来区分癌症基因组中突变和选择的影响。对于这一系列大量的公开可用癌细胞系，广泛的拷贝数、基因分型、序列和表达数据使其成为未来癌症生物学和药物发现研究的有用试剂。
