Chen Zhenbin, Feng Jinong, Buzin Carolyn H, Sommer Steve S
Department of Molecular Genetics, City of Hope National Medical Center, Duarte, CA, USA.
PLoS One. 2008;3(11):e3714. doi: 10.1371/journal.pone.0003714. Epub 2008 Nov 13.
Evidence strongly suggests that spontaneous doublet mutations in normal mouse tissues generally arise from chronocoordinate events. These chronocoordinate mutations sometimes reflect "mutation showers", which are multiple chronocoordinate mutations spanning many kilobases. However, little is known about mutagenesis of doublet and multiplet mutations (domuplets) in human cancer. Lung cancer accounts for about 25% of all cancer deaths. Herein, we analyze the epidemiology of domuplets in the EGFR and TP53 genes in lung cancer. The EGFR gene is an oncogene in which doublets are generally driver plus driver mutations, while the TP53 gene is a tumor suppressor gene with a more typical situation in which doublets derive from a driver and passenger mutation.
METHODOLOGY/PRINCIPAL FINDINGS: EGFR mutations identified by sequencing were collected from 66 published papers and our updated EGFR mutation database (www.egfr.org). TP53 mutations were collected from IARC version 12 (www-p53.iarc.fr). For EGFR and TP53 doublets, no clearly significant differences in race, ethnicity, gender and smoking status were observed. Doublets in the EGFR and TP53 genes in human lung cancer are elevated about eight- and three-fold, respectively, relative to spontaneous doublets in mouse (6% and 2.3% versus 0.7%).
CONCLUSIONS/SIGNIFICANCE: Although no one characteristic is definitive, the aggregate properties of doublet and multiplet mutations in lung cancer are consistent with a subset derived from chronocoordinate events in the EGFR gene: i) the eight frameshift doublets (present in 0.5% of all patients with EGFR mutations) are clustered and produce a net in-frame change; ii) about 32% of doublets are very closely spaced (< or =30 nt); and iii) multiplets contain two or more closely spaced mutations. TP53 mutations in lung cancer are very closely spaced (< or =30 nt) in 33% of doublets, and multiplets generally contain two or more very closely spaced mutations. Work in model systems is necessary to confirm the significance of chronocoordinate events in lung and other cancers.
有强有力的证据表明，正常小鼠组织中的自发双突变通常源于时间协调事件。这些时间协调突变有时反映“突变簇”，即跨越许多千碱基的多个时间协调突变。然而，对于人类癌症中双突变和多突变（多联体突变）的诱变情况知之甚少。肺癌约占所有癌症死亡人数的25%。在此，我们分析肺癌中表皮生长因子受体（EGFR）和肿瘤蛋白p53（TP53）基因多联体突变的流行病学情况。EGFR基因是一种癌基因，其中双突变通常是驱动突变加驱动突变，而TP53基因是一种肿瘤抑制基因，其更典型的情况是双突变源于一个驱动突变和一个乘客突变。
方法/主要发现：通过测序鉴定的EGFR突变从66篇已发表论文和我们更新的EGFR突变数据库（www.egfr.org）中收集。TP53突变从国际癌症研究机构（IARC）第12版（www-p53.iarc.fr）中收集。对于EGFR和TP53双突变，在种族、民族、性别和吸烟状况方面未观察到明显的显著差异。与小鼠中的自发双突变相比，人类肺癌中EGFR和TP53基因的双突变分别升高了约8倍和3倍（6%和2.3%对0.7%）。
结论/意义：尽管没有一个特征是决定性的，但肺癌中双突变和多突变的总体特性与源自EGFR基因时间协调事件的一个子集一致：i）八个移码双突变（存在于所有EGFR突变患者的0.5%中）聚集并产生净读框内变化；ii）约32%的双突变间隔非常紧密（≤30个核苷酸）；iii）多突变包含两个或更多间隔紧密的突变。肺癌中的TP53突变在33%的双突变中间隔非常紧密（≤30个核苷酸），并且多突变通常包含两个或更多间隔非常紧密的突变。有必要在模型系统中开展工作以证实时间协调事件在肺癌和其他癌症中的重要性。
