Cancer clue: RNA-destroying enzyme may thwart prostate-tumor growth

The size and shape of a walnut, the prostate gland is the source of the fluid that carries a man’s sperm. It’s also a source of great concern to many men: In 2001, physicians in the United States diagnosed nearly 200,000 cases of prostate cancer and more than 30,000 men died of the disease.

By studying families that include several men with prostate cancer, scientists have now identified a tumor-suppressing gene on chromosome 1. It’s unclear whether mutations in this eagerly sought gene will ultimately explain many cases of prostate cancer, but investigators are optimistic that their work has revealed a novel facet of tumor-cell biology. Also, they say, the finding could suggest new ways of diagnosing or treating prostate cancer.

Although newly associated with prostate cancer, the gene has been studied since the 1970s. It encodes an enzyme known as RNase L, which degrades RNA, a chemical relative of DNA. Linking defects in this gene to prostate cancer is “the first example where RNA turnover is implicated in tumor suppression,” says Robert H. Silverman of the Cleveland Clinic Foundation.

Silverman has investigated RNase L for most of his career. Last year, he got an unexpected phone call from a group of geneticists who had been tracking down a hereditary prostate cancer gene on chromosome 1 since 1996. The geneticists, led by John Carpten of the National Human Genome Research Institute in Bethesda, Md., told Silverman that they had found inherited mutations in the gene for RNAse L in two families plagued by prostate cancer. The researchers, including Silverman, now reveal their findings in the February Nature Genetics.

The most widely recognized duty of RNase L is to suppress infections by degrading viral and cellular RNA, but there have been hints that the enzyme limits tumor growth. RNase L helps damaged cells commit suicide, which is one way the body defends itself against both cancer and viral infections.

“I hope people working on other types of cancer will now put [the gene for] RNase L on the list of genes they look at,” says Silverman.

In the new study, the men with prostate cancer had inherited mutations in one of their two copies of the enzyme’s gene. Then, a spontaneous mutation in a prostate cell must have deactivated the other copy, permitting the cell to avoid suicide and divide without limits.

Of eight families the geneticists suspected of having a prostate cancer-causing gene on chromosome 1, only two have so far revealed mutations in the gene for

RNase L, Carpten and his colleagues report. They continue to look for disabling mutations in the gene in the other families.

The gene for RNAse L is only the second gene to be identified for hereditary prostate cancer, which makes up about 10 percent of cases. The first has so far accounted for only a few prostate cancer-prone families and is not commonly mutated in men who develop prostate cancer without a family history of the disease (SN: 10/7/00, p. 230).

While the gene for RNase L may similarly explain just a small fraction of prostate cancer cases, its protein could offer insight into more-general causes of the cancer and perhaps an avenue to treat it. Researchers have also struggled to distinguish unthreatening prostate tumors that grow slowly from those that quickly kill a man. Measuring the activity of RNase L in tumors might provide another clue for such crucial diagnoses.

The new study is “simultaneously exciting and disappointing,” says cancer geneticist Timothy Rebbeck of the University of Pennsylvania School of Medicine in Philadelphia. “It’s a very interesting finding, but we need to find out a lot more about this gene before we understand its role in hereditary prostate cancer or prostate cancer in general.”

To that end, Carpten and his colleagues plan to join geneticists at Howard University in Washington, D.C., to study the gene in about 60 African-American families with a strong history of prostate cancer. African-American men, for reasons largely unknown, are much more likely than men in most other ethnic groups to develop prostate cancer and die from it.

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