Abstract : Germline mutations in BRCAl lead to an increased risk of breast and ovarian cancer, with loss of the second, normal allele critical to tumorigenesis. It was widely presumed that the cloning and characterization of genes involved in hereditary breast cancer would lead to a better understanding of the genesis of the more common non-inherited forms of breast cancer. In several ways, BRCAl fits the classic tumor suppressor model. Still, the relative lack of somatic mutations found in BRCAl has argued against its involvement in non-inherited breast cancer. Our research specifically addresses whether transcript-specific regulation of BRCAl, CpG methylation, or large genomic rearrangements are responsible for somatic inactivation of BRCAl. As neither transcript-specific regulation nor CpG methylation appeared to explain the lack of BRCAl somatic mutations, we have chosen to focus on whether BRCAl is inactivated somatically by large genomic rearrangement. Despite the fact that our series of breast tumor/normal tissues is typical in the degree of LOH detected within the BRCAl region, no large rearrangements have been detected using long range PCR. It is premature to draw conclusions as we have not finished Southern analysis in this group of tumors. Nonetheless, if no large somatic rearrangements are detected using both long range PCR and Southern analysis, then we must conclude that BRCAl is not likely to be inactivated by mutation in sporadic breast tumors.