Moolgavkar S H
Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.
Princess Takamatsu Symp. 1991;22:381-91.
The concept of multistage carcinogenesis is one of the central dogmas of cancer research today. Recent laboratory work suggests that many specific genetic changes are associated with carcinogenesis. At the same time, there is increasing evidence that cell proliferation kinetics are important in carcinogenesis. In 1971, Knudson proposed his now celebrated two-mutation model for embryonal tumors. In fact, a two-mutation model that explicitly considers cell kinetics is the most parsimonious model consistent with the incidence of both childhood and adult cancer in human populations. This model has been known to be consistent, as well, with other epidemiologic and experimental data. But can such a model be reconciled with the laboratory evidence suggesting that many genetic alterations are required for malignant transformation? In this paper, I examine multistage carcinogenesis from the population perspective. Can cancer incidence data in populations provide some insight into the number and nature of stages involved in malignant transformation? I focus attention on carcinoma of the colon because of the considerable amount of information that is now available on the genetics of these tumors. Also, as is the case with retinoblastoma, colon cancer occurs in sporadic and dominantly inherited forms. A comparison of the incidence of these two forms of colon cancer suggests that mutation at the familial adenomatous polyposis (FAP) locus is not necessary for colon cancer, and that inheritance of the gene for FAP is not equivalent to inheriting one of the essential steps on the pathway to colon cancer. Thus, colon cancer does not follow the retinoblastoma paradigm. The incidence of colon cancer in the general population and among polyposis subjects is consistent with two or three mutations on the pathway to malignancy. A three-mutation model is more consistent with the genetic alterations observed in colon carcinogenesis. I present and discuss a working model for colon cancer.
多阶段致癌作用的概念是当今癌症研究的核心信条之一。最近的实验室研究表明，许多特定的基因变化与致癌作用相关。与此同时，越来越多的证据表明细胞增殖动力学在致癌过程中很重要。1971年，克努森提出了他现在著名的胚胎肿瘤双突变模型。事实上，一个明确考虑细胞动力学的双突变模型是与人类儿童和成人癌症发病率一致的最简约模型。众所周知，这个模型也与其他流行病学和实验数据一致。但是，这样一个模型能否与表明恶性转化需要许多基因改变的实验室证据相协调呢？在本文中，我从人群角度研究多阶段致癌作用。人群中的癌症发病率数据能否为恶性转化所涉及的阶段数量和性质提供一些见解呢？我将注意力集中在结肠癌上，因为现在有大量关于这些肿瘤遗传学的信息。此外，与视网膜母细胞瘤一样，结肠癌也以散发性和显性遗传形式出现。对这两种形式结肠癌发病率的比较表明，家族性腺瘤性息肉病（FAP）位点的突变对于结肠癌并非必要，并且FAP基因的遗传并不等同于继承结肠癌发生途径中的一个关键步骤。因此，结肠癌并不遵循视网膜母细胞瘤模式。普通人群和息肉病患者中结肠癌的发病率与恶性转化途径上的两到三个突变一致。一个三突变模型与在结肠癌发生过程中观察到的基因改变更一致。我提出并讨论了一个结肠癌的工作模型。
