Tumor progression. When a brain tumor loses its PTEN genes, a low-grade cancer (right) is likely to turn highly malignant (left).

Key Gene Behind Deadly Cancers Nabbed

Scientists have discovered a gene, the inactivation of which may help take the brakes off the development of several major cancers, including those of the brain and prostate. The stunning finding, reported by one team in tomorrow's issue of Science and by a second in next month's Nature Genetics, may help oncologists predict who might be at high risk for these cancers and also whose brain or prostate tumors will be highly malignant--information that could help clinicians decide how aggressive they should be with surgery, chemotherapy, or other treatments.

The researchers began their hunt on chromosome 10 because they knew that this chromosome is completely or partially missing in a variety of cancers, especially aggressive brain tumors called gliomas--a prime indication that it carries a tumor suppressor. To narrow down the location of the suspected gene, a team led by Ramon Parsons at Columbia University's College of Physicians and Surgeons and Michael Wigler of Cold Spring Harbor Laboratory on Long Island compared equivalent sections of DNA from normal cells and cells from 65 human breast cancers. They found that one genetic marker was missing in two breast cancer samples, as well as from some prostate and brain tumor cell lines. Comparing fragments of the target gene flagged by the marker to a database of short DNA pieces called expressed sequence tags, the researchers were able to piece together the whole gene. Their description of the gene, dubbed PTEN (for phosphatase and tensin homolog deleted on chromosome 10), appears in Science.

The other group, led by cell biologist Peter Steck of M. D. Anderson Cancer Center in Houston and Sean Tavtigian of the biotech firm Myriad Genetics in Salt Lake City, tracked down the same gene in brain tumor cells. They called it MMAC1 (for mutated in multiple advanced cancers 1), and will publish a report in Nature Genetics. "We started from two different places for two different reasons and got to the same place at the same time," says Steck.

The new gene joins some 16 other known tumor suppressors. But while it's far from the first such gene discovered, cancer researchers are enthusiastic, because the early data indicate that PTEN might rank in importance with p53 and other tumor suppressors that have been linked to several tumor types. "[PTEN] seems to be a major gene in some pretty important cancers," says Kenneth Kinzler, a molecular geneticist at Johns Hopkins University. In addition to prostate cancer, which afflicts some 317,000 men every year in the United States, and gliomas, which strike another 15,000 people, these might include breast and kidney cancer.

Researchers still have a lot to do to find out just how the gene's loss could contribute to these cancers, although its sequence provides some important clues. The PTEN protein appears to be a phosphatase enzyme that may counteract the work of the growth-stimulating kinases, which can help make cells cancerous when they are mutated into an overactive form. Thus, PTEN's loss may lead to excess cell growth. Loss of the gene might also help cancer cells invade other tissues, in which case assessing PTEN's status might help predict a tumor's malignancy. Says Steck, "If you had a molecular marker that could aid a clinician in that decision, that would be very significant."