Genetic counselling in breast cancer: sensitivity to parameter values and to available information

Most segregation analyses have concluded that breast cancer results from a mixture of sporadic and genetic cases. Genetic cases are probably due to a rare inherited mutation with autosomal dominant transmission. The lifetime risk for female mutation carriers is close to 1, ten fold greater than for noncarriers. Beyond these accepted results, studies differ in the estimated parameters specifying the correspondence between phenotypes and genotypes. We show here that these differences have an impact on the estimation of the probability that a woman is carrying a mutation given her disease status and also given the information on the disease status of her family members. We illustrate this problem by computing the probability of being a mutation carrier for 16 women (9 affected, 7 unaffected) belonging to one pedigree, using three sets of parameter values. For two of the women, the probability that they inherited the mutation is low, but it varies considerably according to the set of parameter values. For one woman, the probability varies from 20 to 60% if familial information is taken into account. Segregation of 17q markers in families may provide additional information depending on the posterior probability of linkage. Indeed in the pedigree studied here, the segregation of 17q markers provided additional information which moreover decreased the sensitivity to the parameters values. However, the decrease in sensitivity will only be observed if the posterior probability of linkage of the family to the studied markers is high.