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

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 aggreg ation of the disease. To study the possible additional genetic components, we conducted single-locus and two-locus segregation analyses, with and with out a polygenic background, using three-generation families ascertained thr ough 858 women with breast cancer diagnosed at age <40 years, ascertained t hrough population cancer registries in Melbourne and Sydney, Australia. Ext ensive testing for deleterious mutations in BRCA1 and BRCA2, to date, has i dentified 34 carriers. Our analysis suggested that, after other possible un measured familial factors are adjusted for and the known BRCA1 and BRCA2 mu tation carriers are excluded, there appears to be a residual dominantly inh erited risk of female breast cancer in addition to that derived from mutati ons in BRCA1 and BRCA2. This study also suggests that there is a substantia l recessively inherited risk of early-onset breast cancer. According to the best-fitting model, after excluding known carriers of mutations in BRCA1 a nd BRCA2, about 1/250 (95% confidence interval [CI] 1/500 to 1/125) women h ave 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 nov el strong recessive effect include our inclusion of data on lineal aunts an d grandmothers, study of families ascertained through women with early-onse t breast cancer, allowance for multiple familial factors in the analysis, a nd 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 canc er-susceptibility genes.