Cancer genes: whence malignant power?

Cancer genes: Whence malignant power?

Within the chromosomes of any normal cell are DNA sequences almost identical to those associated with various cancers. Scientists have two major hypotheses to explain why these sequences sometimes initiate malignancies. One is that the sequences become overactive, creating abnormally high levels of crucial growth-controlling proteins. The other is that a minor difference--a single nucleotide change, or "point mutation'--in the DNA sequence turns a normal gene into a potent cell-transforming agent. But some scientists now argue, against the prevailing models, that a major restructuring of a gene must occur to trigger cancer.

"A cell doesn't contain "cancer genes.' Only after considerable structural change does a cellular sequence become a cancer gene,' says Peter H. Duesberg of the University of California at Berkeley. "The point mutation is just a tune-up.'

In the April PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (No. 8), Duesberg and Klaus Cichutek report that reversing the single nucleotide changes in cancer-causing DNA segments known as ras genes, which were then packaged in viruses, did not prevent them from transforming cells.

Duesberg and Cichutek propose that a DNA region "upstream' of the ras gene is actually a crucial part of the normal cellular gene that corresponds to ras. The ras gene is composed of four coding regions called exons, numbered 1 to 4, separated by noncoding regions called introns. The Berkeley scientists now propose that there is a fifth exon, which they call exon--1, whose outer boundary has not yet been identified. This newly proposed exon, either by encoding a currently unknown protein segment or by containing regulatory functions, is essential to normal cell growth, they say. It is the truncation of this region, either by a cancer-causing virus encasing a segment of normal DNA or by molecular biologists isolating the ras gene, that confers malignant power.

Other scientists working on ras genes are skeptical, or even incensed, by Duesberg's proposal. One says the data supporting the role of point mutations in cancer-gene activation are so strong that no further explanation is needed. Another says determinations of DNA sequence now under way are likely to prove Duesberg wrong. Meanwhile, Cichutek and Duesberg plan to locate the other end of exon--1 and see whether it can prevent the other exons from triggering cancer.