Estimating the power of linkage analysis in hereditary breast cancer

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.