Narod S A, Amos C
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Am J Hum Genet. 1990 Feb;46(2):266-72.
Because evidence from several sources suggests the existence of a major genetic factor contributing to the risk for breast cancer, there is current interest in searching for genetic linkage between the putative cancer susceptibility gene(s) and polymorphic DNA markers. However, because of high population rates of the nongenetic form of the condition, and because of the possibility of underlying genetic heterogeneity, it is expected that the number of informative families required for detection of linkage will be greater for breast cancer than for other conditions with major genetic components. Computer simulation approaches may be useful in estimating the power of proposed linkage studies. Here we have simulated multiple genotypes for a medium-sized breast-cancer family and have analyzed the generated pedigrees with a linkage program. The effects of possible phenocopies and of genetic heterogeneity were measured by comparing the results obtained when the parameters were varied in the models. When population-based rates for sporadic cases of breast cancer were incorporated, the number of families required to detect linkage was approximately twice that expected in the absence of phenocopies. Incorrect specification of the probability of phenocopies in the analytic model did not materially alter the power of the proposed study, although significant effects on the estimated recombination fractions were noted.
由于来自多个来源的证据表明存在一个导致乳腺癌风险的主要遗传因素，目前人们对寻找假定的癌症易感基因与多态性DNA标记之间的遗传连锁关系很感兴趣。然而，由于该疾病非遗传形式在人群中的发病率很高，并且存在潜在遗传异质性的可能性，预计检测乳腺癌连锁所需的信息丰富的家系数量将比其他具有主要遗传成分的疾病更多。计算机模拟方法可能有助于估计拟进行的连锁研究的效能。在此，我们为一个中等规模的乳腺癌家系模拟了多种基因型，并使用一个连锁程序分析了生成的系谱。通过比较模型中参数变化时获得的结果，测量了可能的表型模拟和遗传异质性的影响。当纳入基于人群的散发性乳腺癌发病率时，检测连锁所需的家系数量约为无表型模拟时预期数量的两倍。尽管注意到对估计的重组分数有显著影响，但分析模型中表型模拟概率的错误设定并未实质性改变拟进行研究的效能。
