Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study

We used data from a population based series of breast cancer patients to in vestigate the genetic models that can best explain familial breast cancer n ot due to the BRCA1 and BRCA2 genes. The data set consisted of 1,484 women diagnosed with breast cancer under age 55 registered in the East Anglia Can cer registry between 1991-1996. Blood samples taken from the patients were analysed for mutations in BRCA1 and BRCA2. The genetic models were construc ted using information on breast and ovarian cancer history in first-degree relatives and on the mutation status of the index patients. We estimated th e simultaneous effects of BRCA1, BRCA2, a third hypothetical gene BRCA3, an d a polygenic effect. The models were assessed by likelihood comparisons an d by comparison of the observed numbers of mutations and affected relatives with the predicted numbers. BRCA1 and BRCA2 could not explain all the fami lial clustering of breast cancer. The best-fitting single gene model for BR CA3 was a recessive model with a disease allele frequency 24% and penetranc e 42% by age 70. However, a polygenic model gave a similarly good fit. The estimated population frequencies for BRCA1 and BRCA2 mutations were similar under both recessive and polygenic models, 0.024 and 0.041%, respectively. A dominant model for BRCA3 gave a somewhat worse fit, although the differe nce was not significant. The mixed recessive model was identical to the rec essive model and the mixed dominant very similar to the polygenic model. Th e BRCA3 genetic models were robust to the BRCA1 and BRCA2 penetrance assump tions. The overall fit of all models was improved when the known effects of parity on breast and ovarian cancer risks were included in the model-in th is case a polygenic model fits best. These findings suggest that a number o f common, low-penetrance genes with additive effects may account for the re sidual non-BRCA1/2 familial aggregation of breast cancer, but Mendelian inh eritance of an autosomal recessive allele cannot be ruled out. (C) 2001 Wil ey-Liss, Inc.