After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer

Abstract

Mutations in BRCA1 and BRCA2 that cause a dominantly inherited high risk of female breast cancer seem to explain only a small proportion of the aggregation of the disease. To study the possible additional genetic components, we conducted single-locus and two-locus segregation analyses, with and without a polygenic background, using three-generation families ascertained through 858 women with breast cancer diagnosed at age <40 years, ascertained through population cancer registries in Melbourne and Sydney, Australia. Extensive testing for deleterious mutations in BRCA1 and BRCA2, to date, has identified 34 carriers. Our analysis suggested that, after other possible unmeasured familial factors are adjusted for and the known BRCA1 and BRCA2 mutation carriers are excluded, there appears to be a residual dominantly inherited risk of female breast cancer in addition to that derived from mutations in BRCA1 and BRCA2. This study also suggests that there is a substantial recessively inherited risk of early-onset breast cancer. According to the best-fitting model, after excluding known carriers of mutations in BRCA1 and BRCA2, about 1/250 (95% confidence interval [CI] 1/500 to 1/125) women have a recessive risk of 86% (95% CI 69%-100%) by age 50 years and of almost 100% by age 60 years. Possible reasons that our study has implicated a novel strong recessive effect include our inclusion of data on lineal aunts and grandmothers, study of families ascertained through women with early-onset breast cancer, allowance for multiple familial factors in the analysis, and removal of families for whom the cause (i.e., BRCA1 or BRCA2) is known. Our findings may have implications for attempts to identify new breast cancer-susceptibility genes.

Figure 1

Three-generation family, ascertained through a proband with breast cancer at age <40 years, showing age at onset, death, or interview, that gives most support for a recessively inherited risk of breast cancer. The proband has not been found to carry a germline mutation in either BRCA1 or BRCA2.

Figure 2

Age-specific cumulative probability of breast cancer for the population, and for sisters, mothers and lineal aunts of the probands who had breast cancer before age 40 years.

Figure 3

Age-specific cumulative probabilities of breast cancer for the population, for carriers of a dominantly inherited and a recessively inherited risk, and for noncarriers of the recessively inherited risk, with 95% CIs, on the basis of the 824 families with known BRCA1 and BRCA2 mutation carriers and their relatives excluded, under the multiplicative two-locus model.