Hereditary breast and ovarian cancer and the BRCA1 gene.

Abstract

Breast cancer ranks first in incidence and second in mortality rates of all cancers among women in Western countries. While the lifetime risk for breast cancer in the general population is approximately 10%, this estimate approaches 50% at age 65 when high-risk families are considered. Inherited breast cancer accounts for 5 to 10% of all breast cancers. Previous epidemiological and molecular studies have supported the existence of one or more tumor suppressor genes segregating in these families. A major gene responsible for early-onset breast and ovarian cancer (BRCA1) was linked to chromosome 17q12- 21, and accounts for about 45% of families with inherited breast cancer and 90% of families with both breast and ovarian cancers. Further genetic studies narrowed the candidate interval to approximately 1 cM. This work describes the use of positional cloning approaches to the BRCA1 candidate region. A physical map, consisting of a minimal contig of 45 cosmid and 3 P1 clones spanning most of the BRCA1 candidate region, is presented. These clones were used for the construction of a transcript map containing at least 26 genes. From the six gene-identification techniques used in this work, exon amplification was the most productive, generating 76 exon clones in 650 kb analyzed. Among the genes studied, the structural characterization and tissue expression of a novel gene (Tsp23) with homology to p23, a subunit of the progesterone receptor complex, is described in detail. The BRCA1 gene was identified by Skolnick and collaborators in 1994. With the dual goal of confirming the identity of the BRCA1 gene and estimating the distribution of mutations in the coding region, a collection of 49 at-risk kindreds were analyzed for mutations using the single-strand conformation polymorphism (SSCP) technique. A total of six sequence alterations which are predicted to result in a truncated protein were identified. Three additional missense alterations were also identified. Future goals for the understanding of the biochemical properties of BRCA1 and its role in tumor proliferation are discussed, including (1) the characterization of the possible functional significance of a predicted RING finger, (2) the generation of antibodies against BRCA1 protein to determine its cellular localization, (3) the use of the differential display technique to identify genes regulated by BRCA1, (4) the generation of an animal model to study the potential interaction of BRCA1 with other cell-growth regulator genes, and (5) the development of therapies which could suppress tumor proliferation and improve the survival rate in carriers for BRCA1 mutations.