Luebeck E Georg, Moolgavkar Suresh H
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, P.O. Box 19024, Seattle, WA 98109-1024, USA.
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15095-100. doi: 10.1073/pnas.222118199. Epub 2002 Nov 1.
We use general multistage models to fit the age-specific incidence of colorectal cancers in the Surveillance, Epidemiology, and End Results registry, which covers approximately 10% of the U.S. population, while simultaneously adjusting for birth cohort and calendar year effects. The incidence of colorectal cancers in the Surveillance, Epidemiology, and End Results registry is most consistent with a model positing two rare events followed by a high-frequency event in the conversion of a normal stem cell into an initiated cell that expands clonally to give rise to an adenomatous polyp. Only one more rare event appears to be necessary for malignant transformation. The two rare events involved in initiation are interpreted to represent the homozygous loss of adenomatous polyposis coli gene function. The subsequent transition of a preinitiated stem cell into an initiated cell capable of clonal expansion via symmetric division is predicted to occur with a frequency too high for a mutational event but may reflect a positional effect in colonic crypts. Our results suggest it is not necessary to invoke genomic instability to explain colorectal cancer incidence rates in human populations. Temporal trends in the incidence of colon cancer appear to be dominated by calendar year effects. The model also predicts that interventions, such as administration of nonsteroidal anti-inflammatory drugs, designed to decrease the growth rate of adenomatous polyps, are very efficient at lowering colon cancer risk substantially, even when begun later in life. By contrast, interventions that decrease the rate of mutations at the adenomatous polyposis coli locus are much less effective in reducing the risk of colon cancer.
我们使用通用多阶段模型来拟合监测、流行病学和最终结果登记处中结直肠癌的年龄别发病率，该登记处覆盖了约10%的美国人口，同时对出生队列和日历年效应进行了调整。监测、流行病学和最终结果登记处中结直肠癌的发病率与一个模型最为一致，该模型假定在正常干细胞转化为起始细胞并克隆性扩增以产生腺瘤性息肉的过程中，有两个罕见事件，随后是一个高频事件。恶性转化似乎仅需再发生一个罕见事件。起始过程中涉及的两个罕见事件被解释为代表腺瘤性息肉病大肠杆菌基因功能的纯合缺失。预测预先起始的干细胞随后通过对称分裂转变为能够克隆性扩增的起始细胞的频率对于突变事件来说过高，但可能反映了结肠隐窝中的位置效应。我们的结果表明，没有必要援引基因组不稳定性来解释人群中的结直肠癌发病率。结肠癌发病率的时间趋势似乎主要由日历年效应主导。该模型还预测，旨在降低腺瘤性息肉生长速度的干预措施，如使用非甾体抗炎药，即使在生命后期开始，也能非常有效地大幅降低结肠癌风险。相比之下，降低腺瘤性息肉病大肠杆菌基因座突变率的干预措施在降低结肠癌风险方面效果要差得多。
