Department of Ecology and Evolution, The University of Chicago, 1101 East 57th Street, Chicago, IL 60637, USA.
Nat Commun. 2012;3:1004. doi: 10.1038/ncomms1982.
Cancer cells evolve from normal cells by somatic mutations and natural selection. Comparing the evolution of cancer cells and that of organisms can elucidate the genetic basis of cancer. Here we analyse somatic mutations in >400 cancer genomes. We find that the frequency of somatic single-nucleotide variations increases with replication time during the S phase much more drastically than germ-line single-nucleotide variations and somatic large-scale structural alterations, including amplifications and deletions. The ratio of nonsynonymous to synonymous single-nucleotide variations is higher for cancer cells than for germ-line cells, suggesting weaker purifying selection against somatic mutations. Among genes with recurrent mutations only cancer driver genes show evidence of strong positive selection, and late-replicating regions are depleted of cancer driver genes, although enriched for recurrently mutated genes. These observations show that replication timing has a prominent role in shaping the single-nucleotide variation landscape of cancer cells.
癌细胞通过体细胞突变和自然选择从正常细胞中进化而来。比较癌细胞和生物体的进化可以阐明癌症的遗传基础。在这里，我们分析了超过 400 个癌症基因组中的体细胞突变。我们发现，体细胞单核苷酸变异的频率在 S 期的复制时间内比种系单核苷酸变异和体细胞大规模结构改变（包括扩增和缺失）增加得更为剧烈。与种系细胞相比，癌症细胞中非同义单核苷酸变异与同义单核苷酸变异的比值更高，这表明体细胞突变受到的纯化选择较弱。在具有反复突变的基因中，只有癌症驱动基因显示出强烈的正选择证据，而晚期复制区域则缺乏癌症驱动基因，尽管富含反复突变的基因。这些观察结果表明，复制时间在塑造癌细胞中单核苷酸变异景观方面起着重要作用。
