Cancer risk linked to increased DNA mix-ups.

Genomic instability -- the tendency of DNA to get mixed up and for genes to mutate -- underlies evolutionary change and makes possible varied immune responses against infections. But this tendency can also get cells in trouble and ultimately lead to cancer.

An analysis of genetic activity in people with an inherited defect that predisposes them to malignant tumors now strongly supports this notion. Also, a new test may make it possible to assess DNA mix-ups in large groups of people.

"If we can measure genetic instability, then we might be able to gain insight into the risk of that individual or that population to develop cancer," says Ilan Kirsch of the National Cancer Institute-Navy Oncology Branch in Bethesda, Md.

Finally, evidence is building that problems concerning the tumor-suppressor gene p53 (SN: 5/16/92, p.324) may exacerbate this instability and predispose a cell to uncontrolled division.

The cancer-predisposing genetic disease, called ataxia- telangiectasia (A-T), leads not only to tumors but also to problems with nerves and the immune system. This presumably results because genes fail to rearrange and generate a diverse array of antibodies, says M. Stephen Meyn, a clinical geneticist at Yale University School of Medicine. Cells in people with A-T are also very susceptible to ionizing radiation.

But Meyn's study shows that genes within chromosomes of people with A-T play molecular musical chairs -- moving around at rates 30 to 200 times higher than those of normal cells, he says.

Unlike previous investigators, who evaluated rearrangements in free-floating DNA inserted into cells and saw little increase in these rearrangements, Meyn waited until that DNA became incorporated into the cell's own chromosomes. In one experiment, the DNA insert contained two defective copies of a gene that, when repaired, enables cells to resist the killing effects of an antibiotic. In another, the insert contained two defective copies of a gene that, if repaired, makes cells blue. The large number of surviving cells or the number of blue cells revealed the high frequency of mix-ups, he reports in the May 28 SCIENCE.

"In these high rates of recombination, one finds a ready explanation for why A-T patients get cancer," Meyn concludes.

The high rate of DNA mix-ups seen by Meyn parallels observations by Kirsch and his colleagues, who use a very different measure of genomic instability. These researchers focus on mix-ups that occur between two pieces of chromosome 7, whose DNA is active in white blood cells. The mix-up causes the cells to make a hybrid molecule consisting of parts of two separate immune system proteins, presumably because pieces of the proteins' respective genes have fused.

The scientists use the polymerase chain reaction--a means of detecting tiny amounts of a specific piece of DNA -- to determine when these two gene fragments link up. The test requires only a few drops of blood -- whatever oozes from a typical finger-stick test, Kirsch says.

Such rearrangements should occur rarely between genes: in one in 5,000 to one in 50,000 cells, Kirsch says. But people with A-T have 100 times the number of these mix-ups, he reported in mid-May in Orlando, Fla., at the American Association for Cancer Research meeting. These people also run about 100 times the risk of developing cancer.

Kirsch and Vincent Garry of the University of Minnesota in Minneapolis have also tested a dozen midwestern farmers from regions with unusually high rates of leukemia and lymphoma. On average, the farmers had about four times the normal number of mix- ups in this DNA, they found. Furthermore, the farmers who bought and used the most pesticides also had the greatest genomic instability, says Kirsch. That instability increased in summer and declined in winter.

"If this [study] is confirmed, then [this test] seems to be detecting not just a genetic predisposition to genomic instability but a predisposition that is environmentally produced," Kirsch says.

Yet this predisposition does not necessarily lead to cancer. Tumors result when cells also lose their ability to repair DNA damage before they make more copies of their chromosomes or pass that genetic material on to daughter cells. At the Orlando meeting, researchers described how the tumor-suppressor gene p53 becomes active when DNA is damaged. This gene codes for a protein that keeps cells from making new DNA until the genes are repaired. With no p53 gene, cells keep dividing, so the mutated genes multiply rapidly, says Thea D. Tlsty of the University of North Carolina at Chapel Hill.

As a cell makes copies of faulty DNA, it creates more faults, which themselves cause more mix-ups to occur, accelerating the mutation rate, notes Meyn. Such mutations might lead to uncontrolled, malignant cell growth.

Tlsty has examined gene amplification, in which cells make multiple copies of a particular gene, and has observed that this process occurs in about one in a billion healthy cells but in as many as one in 100 tumor cells. Other evidence suggests that the p53 gene plays a role in suppressing amplification in healthy cells and that many types of cells start amplifying their genes in the absence of p53 genes, Tlsty says.

COPYRIGHT Science Service Inc. 1993