Over the last several years, evidence has accumulated to support the idea that rare Ha-ras polymorphisms are associated with inherited susceptibility to certain human cancers. A recent epidemiologic study conducted at our institution found a significant association specifically with breast cancer, although the mechanism underlying this relationship remains unclear. We have proposed that rare Ha-ras alleles are markers of a genomic instability that predisposes to breast cancer. To address this hypothesis, we are investigating the relationship between the presence of rare alleles and another form of instability, gene amplification, and are developing new methodologies both to improve VNTR allele length detection and to characterize the internal repeat sequence variations of the various alleles. These studies should enable us to more clearly define the role of this region in cancer development by delineating VNTR structure and function and the mechanisms of rare allele generation. Ultimately, we hope to identify VNTR characteristics that will permit more accurate cancer risk assessment.