Hereditary cancer: Two hits revisited
Hereditary cancer: Two hits revisited
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DOI：
10.1007/bf01366952
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发表时间：
1996-03-01
影响因子：
3.6
通讯作者：
Knudson, AG
中科院分区：
文献类型：
--
作者：
Knudson, AG
根据“两次打击”模型，显性遗传的癌症易感性需要种系突变，而肿瘤发生需要第二个体细胞突变。相同类型的非遗传性癌症需要相同的两次命中，但都是体细胞的。在这个模型中使用的原始肿瘤，视网膜母细胞瘤，涉及遗传和非遗传形式的RBI肿瘤抑制基因的两个拷贝的突变或丢失。事实上，大多数显性遗传的癌症都表现出这种关系。然而，新的问题出现了。当肿瘤抑制基因普遍表达时，为什么会有肿瘤偏好的特异性？在某些情况下，很明显，两次击中只产生良性的前驱病变，其他遗传事件是必要的。随着必要事件数量的增加，种系突变的影响逐渐减弱。胚胎性肿瘤的事件数量最少，某些肉瘤相对较少。干细胞增殖显然在癌发生的早期起着关键作用。在某些组织中，它是生理性的，例如在胚胎发育和青春期的某些组织中。在成人更新组织中，常见癌的位点，突变可能是削弱更新和复制细胞分裂之间的切换控制所必需的; APC基因可能是这种突变的靶点。
According to a ''two-hit'' model, dominantly inherited predisposition to cancer entails a germline mutation, while tumorigenesis requires a second, somatic, mutation. Non-hereditary cancer of the same type requires the same two hits, but both are somatic. The original tumor used in this model, retinoblastoma, involves mutation or loss of both copies of the RBI tumor-suppressor gene in both hereditary and non-hereditary forms. In fact, most dominantly inherited cancers show this relationship. New questions have arisen, however. When a tumor-suppressor gene is ubiquitously expressed, why is there any specificity of tumor predilection? In some instances, it is clear that two hits produce only a benign precursor lesion and that other genetic events are necessary. As the number of necessary events increases, the impact of the germline mutation diminishes. The number of events is least for embryonal tumors, and relatively small for certain sarcomas. Stem-cell proliferation evidently plays a key role early in carcinogenesis. In some tissues it is physiological, as in embryonic development and in certain tissues in adolescence. In adult renewal tissues, the sites of the common carcinomas, mutation may be necessary to impair the control of switching between renewal and replicative cell divisions; the APC gene may be the target of such a mutation.