Approximately 5-10 percent of breast cancer is hereditary, and a gene designated BRCA1, which is responsible for the majority of hereditary breast cancers, has been mapped (initially by the applicants) to a very narrow region of chromosome 17q21. By analogy with other hereditary tumors, it is supposed that somatic mutations of BRCA1 are very likely to be involved in the great majority of sporadic breast cancers. In contrast to sporadic tumors, hereditary breast cancer is marked by early onset of the disease, and approximately 40 percent of breast cancers occurring in women <30 years is hereditary.
The specific aims of this application are to clone genes involved in the development of breast and ovarian cancer. The initial goal is to use standard positional cloning techniques to isolate BRCA1 which is now located in an interval <500 kb. The applicants will screen cDNAs already isolated from this interval, and newly identified coding sequences from the region for mutations in early-onset breast cancers to identify the BRCA1 locus. Once the BRCA1 gene is identified, the intron/exon structure will be determined, and assays developed for screening the coding sequences and splice sites for mutations. The germline BRCA1 mutations will then be characterized in all the chromosome 17-linked families, and somatic alterations in the locus will be analyzed in breast tumors at different stages of development. Finally, BRCA1 will be screened in samples from the general population to determine the frequency of mutant alleles. A subset of breast and ovarian cancers are definitely not linked to BRCA1 on chromosome 17. The applicants also propose a standard genome-wide screen using highly informative short sequence repeat polymorphisms to identify linkage for other loci that may be involved in the development of these malignancies.
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