Why Are the Majority of Hereditary Cases of Early-Onset Breast Cancer Sporadic? A Simulation Study

Population-based studies, including those of Ashkenazi Jews, have observed that at least 50% of women with early-onset breast cancer who carry a germ line mutation in BRCA1 or BRCA2 do not report a family history of the disease. That is, the majority of “hereditary” cases are“ sporadic.” Furthermore, the great majority of “familial breast cancers” are not hereditary. We conducted a simulation study to evaluate the probability that a woman with early-onset breast cancer is a mutation carrier, given the number of affected relatives, for a range of plausible values of allele frequency (0.001–0.01), and increased risk in mutation carriers (5–20, equivalent to cumulative risks to age 70 of 25–70%, respectively, for Australian women). Families consisted of a case proband and her mother, sisters, and maternal and paternal grandmothers, and aunts. The numbers of sisters and aunts were generated according to Poisson distributions, and ages were assigned according to a Weibull distribution. The simulated distributions of family history and of the prevalence of mutation carriers among case probands were in general similar to those observed in population-based studies, although there was a suggestion of heterogeneity of breast cancer risk in mutation carriers. As is being observed empirically in population-based samples, a family history of breast cancer was not a strong predictor of mutation status; each affected female relative increased the risk of being a mutation carrier by only 2- to 3-fold. The probability of being a mutation carrier was generally low, except in families with extreme histories of breast cancer.