The idea that cancer is a disease of altered genes was widely discussed among basic scientists in the 1970s. The clinching evidence that brought it to wider attention was the discovery of mutations in the genome of tumour cells that, when transferred into other cells, were sufficient to cause transformation.

By the late 1970s, it was well known that retroviral oncogenes could rapidly transform cells, and that the viruses had acquired these genes from the genomes of the mammalian and avian cells that they infected (see Milestone 15). It was therefore proposed that mutations in the cellular homologues of these genes could transform cells in the absence of any viral involvement, and that this occurred in a substantial proportion of human cancers. Key discoveries by the Robert Weinberg and Geoffrey Cooper groups showed that such transformation could occur when the DNA of a chemically mutagenized transformed mouse cell was transferred. However, the precise identity of the transforming gene was not known, as a lot of irrelevant DNA was also transferred.

Finally, in 1982, the Weinberg, Michael Wigler and Mariano Barbacid groups all cloned the first oncogene, from bladder carcinoma lines, after closing in on the relevant DNA by numerous rounds of transfection. In each round, more of the irrelevant DNA was lost, until the actual oncogene could be cloned with the use of linked sequence tags. These cloned cellular genes had the same transforming properties as the oncogenes from retroviruses.

Having uncovered the presence of cellular oncogenes, attention turned immediately to their identity. Within a few months, the Weinberg and Barbacid groups, as well as Cooper and colleagues, had shown by restriction endonuclease mapping and Southern blotting that the oncogenes in question were the cellular homologues of the ras genes from the Harvey and Kirsten sarcoma viruses.

However, such analysis was not detailed enough to identify any difference between the normal cellular human c-Ha-RAS1 gene and its transforming counterpart from the carcinoma lines. This implied that the two versions of the gene were similar and any sequence difference was subtle. Using an elegant molecular genetics strategy that has since become obsolete, the Weinberg, Barbacid and Wigler groups systematically substituted each restriction fragment from the non-transforming allele with the corresponding one from the transforming allele. In this way, they were able to hone in on the genetic lesion and, by the end of 1982, all three groups had discovered the same single amino-acid change: glycine to valine at position 12. Subsequent research has shown that this change alters the structure of the RAS protein to make it constitutively active.

During just 1 year, not only was the concept of the cellular oncogene confirmed by the cloning of cellular RAS, but the activating mutation was also identified. The developments of 1982 were a crucial step towards the modern understanding of cancer as a complex interplay between different types of genetic lesion.