A LARGE KINDRED WITH 17Q-LINKED BREAST AND OVARIAN-CANCER - GENETIC, PHENOTYPIC, AND GENEALOGICAL ANALYSIS

Background: Mutation of a specific, but as yet unidentified, gene BRCA 1 on chromosome 17q results in increased susceptibility to breast and ovarian cancer. lt is important to know the effects of this gene in te rms of the age-specific risks of these cancers and the potential inter action of this gene with other known risk factors. Purpose: We perform ed detailed studies on a large multi-generational family, in which the re is known 17q-linked breast and ovarian cancer, in order to characte rize the effects of the BRCA1 mutation on development of breast and ov arian cancer. Methods: Data from the Utah Population Database were use d to identify a family (identified as K2082) with a cluster of premeno pausal breast cancer and ovarian cancer at any age. Blood samples from 195 members of the family were obtained and these individuals were ge notyped for a series of four chromosome 17q polymorphic markers. Infor mation on reproductive history, cancer incidence and treatment, and li festyle factors was collected on 72 women in the family by questionnai re or through contact with living relatives. Results: Odds in favor of linkage of breast and ovarian cancer in this family to the BRCA1 regi on of chromosome 17q are greater than 10(8) to 1. The estimated risks for breast or ovarian cancer because of the BRCA1 mutation in this fam ily are 40% by age 50 years and 90% by age 70. No differences between affected and unaffected older BRCA1 gene carriers were observed for a number of known epidemiologic risk factors for these cancers. The gend er of the parent from whom the mutant BRCA1 allele was inherited was s ignificantly associated with phenotypic expression (P = .04). A recomb inant which places BRCA1 distal to the marker Mfd191 was observed. Con clusions: Women with the BRCA1 mutation are at increased risk of devel oping breast and ovarian cancer. In our study population, the mutation appears to confer a lower risk of cancer at younger ages than found i n previous studies. Continued interaction with family K2082 will be us eful in longitudinal follow-up studies and in studies of the psychosoc ial implications of providing DNA diagnosis of BRCA1.