cently made it possible to study human tumors. Two techniques that have been particularly important are the polymerase chain reaction (PCR) and analysis of restriction fragment length polymorphisms (RFLPs). PCR is a method by which any known gene sequence can be specifically amplified so that as few as 10 to 100 copies of a specific sequence can be detected. RFLP analysis allows researchers to distinguish between two alleles of a given gene because of small variations in DNA fragment size that are detected as differences in migration through acrylamide gels after cleavage with site-specific DNAases. One can deduce that a given allele is missing when one fragment is absent from the gel.
Two generalizations are emerging from these molecular characterizations of cancer biopsies that may be relevant to the problem of identifying a possible role for oral contraceptives in the etiology of breast cancer. First, it is clear that the molecular lesions associated with cancers differ depending on the organ of origin. For example, some of the molecular lesions found in colon cancers and certain lung cancers are not detected in breast cancers. This observation provides evidence at the molecular level for the conclusion that different etiologic factors may be responsible for these three common human cancers. Second, among breast cancers there is a great deal of heterogeneity in the types of genetic lesions detected, which suggests that breast cancer may be more than one disease.
The products of ras oncogenes are functionally and structurally similar to the G-proteins. G-proteins normally act by transmitting proliferative signals initiated by extracellular hormones and growth factors. They bind guanine nucleotides and mediate signal transduction through effectors such as adenylate cyclase. Certain mutations in G-proteins induce autonomous activity by inactivating control regions of the protein; these mutations cause loss of cellular growth capability. ras is the only one of the G-protein family that has been extensively studied in human cancers. There are three ras genes, Kl-ras, Ha-ras and N-ras. Mutations at codons 12, 13, or 61 are known to activate each of these ras genes, resulting in transformation of various cell types (for reviews, see Milburn et al., 1990; Bos, 1989).
The overall incidence of ras activation in human cancer has been estimated at 10 to 15 percent. This figure is much higher, however, for specific solid tumors such as adenocarcinomas of the lung (50