Multistage carcinogenesis and the incidence of colorectal cancer
Multistage carcinogenesis and the incidence of colorectal cancer
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DOI：
10.1073/pnas.222118199
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发表时间：
2002-11-12
影响因子：
11.1
通讯作者：
Moolgavkar, SH
中科院分区：
文献类型：
--
作者：
Luebeck, EG;Moolgavkar, SH
我们使用一般的多阶段模型来拟合监测、流行病学和最终结果登记中的结直肠癌的特定年龄发病率，该登记覆盖了大约 10% 的美国人口，同时调整了出生队列和日历年的影响。监测、流行病学和最终结果登记中结直肠癌的发病率与模型最为一致，该模型假定先发生两个罕见事件，然后再发生一个高频事件，将正常干细胞转化为初始细胞，并克隆性扩张，产生腺瘤性息肉。似乎只有另一种罕见事件是恶性转化所必需的。涉及起始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性丧失。预起始干细胞随后转变为能够通过对称分裂进行克隆扩增的起始细胞，预计其发生频率对于突变事件而言过高，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结直肠癌的发病率。结肠癌发病率的时间趋势似乎主要受日历年效应的影响。该模型还预测，旨在降低腺瘤性息肉生长速度的非甾体抗炎药等干预措施，即使在晚年开始，也能非常有效地大幅降低结肠癌风险。相比之下，降低腺瘤性结肠息肉病基因座突变率的干预措施在降低结肠癌风险方面效果较差。
We use general multistage models to fit the age-specific incidence of colorectal cancers in the Surveillance, Epidemiology, and End Results registry, which covers approximate to10% 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.