Ludwig Institute for Cancer Research, São Paulo Branch at Hospital Alemão Oswaldo Cruz, São Paulo 01323-903, Brazil.
Nucleic Acids Res. 2011 Aug;39(14):6056-68. doi: 10.1093/nar/gkr221. Epub 2011 Apr 14.
Although patterns of somatic alterations have been reported for tumor genomes, little is known on how they compare with alterations present in non-tumor genomes. A comparison of the two would be crucial to better characterize the genetic alterations driving tumorigenesis. We sequenced the genomes of a lymphoblastoid (HCC1954BL) and a breast tumor (HCC1954) cell line derived from the same patient and compared the somatic alterations present in both. The lymphoblastoid genome presents a comparable number and similar spectrum of nucleotide substitutions to that found in the tumor genome. However, a significant difference in the ratio of non-synonymous to synonymous substitutions was observed between both genomes (P = 0.031). Protein-protein interaction analysis revealed that mutations in the tumor genome preferentially affect hub-genes (P = 0.0017) and are co-selected to present synergistic functions (P < 0.0001). KEGG analysis showed that in the tumor genome most mutated genes were organized into signaling pathways related to tumorigenesis. No such organization or synergy was observed in the lymphoblastoid genome. Our results indicate that endogenous mutagens and replication errors can generate the overall number of mutations required to drive tumorigenesis and that it is the combination rather than the frequency of mutations that is crucial to complete tumorigenic transformation.
虽然已经报道了肿瘤基因组中的体细胞改变模式，但对于它们与非肿瘤基因组中存在的改变相比如何，人们知之甚少。对这两者进行比较对于更好地描述驱动肿瘤发生的遗传改变至关重要。我们对源自同一患者的淋巴母细胞（HCC1954BL）和乳腺肿瘤（HCC1954）细胞系的基因组进行了测序，并比较了两者中存在的体细胞改变。淋巴母细胞基因组的核苷酸替换数量和类型与肿瘤基因组相似。然而，我们观察到两个基因组中非同义替换与同义替换的比例存在显著差异（P=0.031）。蛋白质-蛋白质相互作用分析显示，肿瘤基因组中的突变优先影响枢纽基因（P=0.0017），并且协同选择呈现协同功能（P<0.0001）。KEGG 分析表明，在肿瘤基因组中，大多数突变基因被组织成与肿瘤发生相关的信号通路。在淋巴母细胞基因组中没有观察到这种组织或协同作用。我们的结果表明，内源性诱变剂和复制错误可以产生驱动肿瘤发生所需的总体突变数量，并且是突变的组合而不是频率对于完成肿瘤转化至关重要。
