张咸宁 消化道肿瘤的遗传学.doc

Lecture Notes 消化道肿瘤的遗传学 张咸宁（细胞生物学与医学遗传学系） 2014/05 I. Causes of Cancer Cells in the body are programmed to develop, grow, differentiate, and die in response to a complex system of biochemical signals. Cancer results from the emergence of a clone of cells freed of these developmental programming constraints and capable of inappropriate proliferation. The basic cause of cancer is damage to specific genes. Usually, mutations in these genes accumulate in somatic cells over the years, until a cell accumulates a sufficient number of errors to initiate a tumor. If damage occurs in cells of the germline（种系）, however, an altered form of one of these genes can be transmitted to progeny and predispose them to cancer. The increased risk of cancer in such persons is due to the fact that each of their cells now carries the first step in a multistep cancer pathway. Environmental factors are known to play important roles in carcinogenesis. However, a person’s overall cancer risk depends on a combination of inherited factors and environmental components. 表1 癌基因与抑癌基因 特点 原癌基因 抑癌基因 基因功能 正常生长和增殖必需 增殖负调控，分化必需 突变（激活）方式 点突变、染色体重排、基因扩增、病毒插入 点突变、LOH等 致癌方式（They behave as） 显性 隐性 突变蛋白的效应 功能失去突变 功能获得突变 遗传方式 体细胞突变，不遗传 体细胞或生殖细胞突变，可遗传 常见于哪些癌肿 白血病、淋巴瘤 实体瘤 Alfred Knudsons “two-hit theory of carcinogenesis”（两次突变假说） in retinoblastoma became the paradigm for a model to describe how inheritance of an altered gene predisposes the gene carrier to cancer. The theory states that a cell can initiate a tumor only when it contains two damaged alleles; therefore, a person who inherits one copy of a mutant retinoblastoma gene must experience a second, somatic mutation in one or more retinoblasts in order to develop one or more retinoblastomas. Two somatic mutations can also occur in a single retinoblast of a nonpredisposed fetus, producing sporadic retinoblastoma. Understanding mutated genes that are inherited in families can increase our understanding of the somatic pathway to common cancers. 但实际上，肿瘤的形成是