Little Mark P, Li Guangquan
Department of Epidemiology and Public Health, Imperial College Faculty of Medicine, London W2 1PG, UK.
Carcinogenesis. 2007 Feb;28(2):479-87. doi: 10.1093/carcin/bgl173. Epub 2006 Sep 14.
Three stochastic models of genomic instability recently developed by Little and Wright (Math. Biosci., (2003) 183, 111-34), with two, three and five stages, and the two-stage genomic instability model of Nowak et al. (Proc. Natl Acad. Sci. USA, (2002) 99, 16226-16231) are compared with the four-stage model proposed by Luebeck and Moolgavkar (Proc. Natl Acad. Sci. USA, (2002) 99, 15095-15100) that does not assume such an instability mechanism. All models are fitted to US colon cancer incidence data. The best fitting models are the two-stage model of Nowak et al. and the two-stage model of Little and Wright, with the four-stage model of Luebeck and Moolgavkar not markedly inferior. The fits of the three-stage and five-stage models are somewhat worse (P<0.05), the five-stage model fitting particularly poorly (P<0.01). Both optimal genomic instability models predict cellular mutation rates that are at least 10 000 times higher after genomic destabilization, for both sexes. Therefore, the results of this paper are somewhat at variance with those of previous analyses of Little and Wright in suggesting that equivalently good fit may be obtained by models that do not assume a role for genomic destabilization in the induction of colon cancer as for those that do.
利特尔和赖特最近开发的三种基因组不稳定性随机模型（《数学生物科学》，（2003年）183卷，111 - 134页），分别有两个、三个和五个阶段，以及诺瓦克等人的两阶段基因组不稳定性模型（《美国国家科学院院刊》，（2002年）99卷，16226 - 16231页），与吕贝克和穆尔加夫卡尔提出的四阶段模型（《美国国家科学院院刊》，（2002年）99卷，15095 - 15100页）进行了比较，后者不假定存在这样的不稳定性机制。所有模型都拟合了美国结肠癌发病率数据。拟合效果最佳的模型是诺瓦克等人的两阶段模型和利特尔与赖特的两阶段模型，吕贝克和穆尔加夫卡尔的四阶段模型也并不明显逊色。三阶段和五阶段模型的拟合效果稍差（P < 0.05），五阶段模型拟合得尤其差（P < 0.01）。两种最优的基因组不稳定性模型预测，在基因组不稳定后，男性和女性的细胞突变率至少比之前高10000倍。因此，本文的结果与利特尔和赖特之前的分析结果有些不同，表明对于结肠癌的诱发，不假定基因组不稳定起作用的模型与假定其起作用的模型可能能获得相当好的拟合效果。
