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Genetic epidemiology of multistage carcinogenesis.

机译:多阶段致癌的遗传流行病学。

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摘要

It is commonly believed that cancer is a multistage, polygenic disease. Even though conceptually appealing, the evidence supporting the multistage theory remains limited. Most known tumor suppresser genes are associated with monogenic dominant cancers following a two-hit pathway. We review results from a recent twin study on 90000 individuals that give support to the multistage theory. Statistically significant heritability estimates were shown for cancers of the colorectum (35%), breast (27%), and prostate (42%). These estimates are much higher than those obtained from family studies in which parents and offspring, or sibs are compared. The difference can be accounted for by the involvement of many genes. A polygenic cancer would show small effects in family studies but large effects in twin studies. We present calculations on the decrease in familial risks when the number of genes involved increases or when the penetrance decreases. We test the apparent number of stages involved in the main cancers from the Swedish Family-Cancer Database. The logarithms of the slopes suggest large differences in the apparent numbers of mutations involved in different cancers. The number of mutations required appears to be less in familial breast cancer compared to sporadic breast cancer. Study designs for gene identification should be revised to accommodate polygenic cancers.
机译:通常认为,癌症是多阶段的多基因疾病。尽管从概念上讲吸引人,但支持多阶段理论的证据仍然有限。大多数已知的抑癌基因与单基因显性癌症相关,涉及两次打击途径。我们回顾了最近一项针对90000个人的双胞胎研究的结果,这些研究为多阶段理论提供了支持。统计表明,对于结直肠癌(35%),乳腺癌(27%)和前列腺癌(42%),遗传力估计值具有统计学意义。这些估计值远高于对父母和后代或同胞进行比较的家庭研究得出的估计值。差异可以通过许多基因的参与来解释。多基因癌症在家庭研究中显示出较小的影响,但在双胞胎研究中显示出较大的影响。当涉及的基因数量增加或外显率降低时,我们对家族风险的降低进行了计算。我们从瑞典家庭癌症数据库测试了涉及主要癌症的明显分期数。斜率的对数表明与不同癌症有关的突变的表观数量差异很大。与散发性乳腺癌相比,家族性乳腺癌中所需的突变数量似乎更少。用于基因鉴定的研究设计应进行修改以适应多基因癌症。

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