Germ-Line BRCA 1 Mutations in Selected Men with Prostate Cancer

To the Editor: Prostate cancer is the most common malignancy among American men (American Cancer Society 1995, pp. 1011). Although the causes of prostate cancer are unknown, a family history of the disease is one of the strongest risk factors identified, to date. Men with an affected first-degree relative with prostate cancer have at least a two-to-three-fold-higher risk of developing the disease compared with men who have no such family history (Carter et al. 1992; Whittemore et al. 1995). Epidemiological observations also suggest a clustering of prostate and breast cancers in some families (Thiessen et al. 1974; Anderson et al. 1992, 1993; Tulinius et al. 1992; Sellers et al. 1994). More specifically, at least two studies suggest that inherited mutations in highly penetrant dominant genes such as BRCA1, which predisposes women to breast and ovarian cancers (Hall et al. 1990; Miki et al. 1994; Easton et al. 1995), may also be associated with an increased risk of prostate cancer in men. In a study of seven large Icelandic breast cancer families, two of which showed evidence of linkage to BRCA1, prostate cancer was found to be the second most frequent malignancy after breast cancer (Arason et al. 1993). Among presumed paternal carriers of mutant breast cancer gene alleles, 44% had a history of prostate cancer. Additional evidence regarding BRCA1 and prostate cancer risk comes from an analysis of 33 BRCA1linked families (Ford et al. 1994). This cooperative study estimated a relative risk of prostate cancer of 3.33 (95% confidence interval 1.8-6.2) among men carrying mutations, compared with the general population. In order to assess directly the potential role of BRCA1 mutations in the etiology of prostate cancer, we have screened for germ-line BRCA1 mutations in a subset of men from an ongoing population-based case-control study of prostate cancer in men <65 years of age. Cancer cases were identified through the Cancer Surveillance System of northwestern Washington State, which is part of the Surveillance, Epidemiology, and End Results program, or SEER, of the National Cancer Institute. Eligible subjects (n = 344) were white or African American men newly diagnosed with histologically confirmed adenocarcinoma of the prostate between January 1, 1993, and June 30, 1994, and who resided in King County, Washington. A total of 280 (81%) of the eligible subjects completed the detailed in-person interview, during which information was collected regarding any family history of malignancies, by primary site, in first-and second-degree relatives. The subgroup of cases selected for this analysis included men in whom genetic factors were most likely to be relevant. Specifically, subjects met at least one of the following criteria: (1) <53 years of age at diagnosis of prostate cancer (n = 32); (2) a family history of breast cancer in a first-degree female relative diagnosed at <51 years of age (n = 13); or (3) a family history of prostate cancer in two or more male relatives, with at least one relative diagnosed at <56 years of age (n = 4). Sixtyone men met one or more of these criteria, and blood samples were available from 49 (80.3%) of them. Characteristics of the interviewed men and the 49 who were genotyped are shown in table 1. These data demonstrate the highly selected nature of the genetic case group with respect to age at diagnosis and family history. In addition, a higher proportion of genotyped subjects had stage C (regional) disease at diagnosis compared with all interviewed cases. In order to estimate the population frequency of each rare BRCA1 allele, genotyping was performed on a series of male controls without a history of prostate can-