BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age

Introduction - A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carr iers frequently have a positive family history of breast and ovarian cancer , are often diagnosed at a young age, and may have a higher incidence of do uble or multiple primary breast tumours than breast cancer patients in gene ral. Objectives - To estimate the prevalence and spectrum of BRCA1 and BRCA2 mut ations in young Danish patients affected with bilateral or multifocal breas t cancer and to determine the relationship of mutation status to family his tory of cancer. Subjects - From the files of the Danish Breast Cancer Cooperative Group (DB CG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease. Methods - DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relativ es of the patients was estimated using data from the Danish Cancer Registry . Results - Twenty four mutation carriers were identified (20%), of whom 13 h ad a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (2 9%) mutation carriers. The mutation frequency was about equal in patients w ith bilateral (22%) and multifocal breast cancer (18%). The incidence of br east and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers. Conclusions - A relatively broad spectrum of germline mutations was observe d in BRCA1 and BRCA2 and most of the mutations are present in other populat ions. Our results indicate that a diagnosis of bilateral and multifocal bre ast cancer is predictive of BRCA1 and BRCA2 mutation status, particularly w hen combined with information on the patients' age at diagnosis and family history of breast/ovarian cancer.