Genes may predict severity of prostate cancer

A four-gene signature has been identified that could help physicians better predict the future course of early-stage prostate cancer, says a new study in Nature.

Prostate cancer is the second most common cancer among U.S. men, with about 217,730 cases diagnosed and 32,050 deaths annually, according to the American Cancer Society.

Most early prostate cancer cases are identified through the prostate-specific antigen test. But once the cancer is identified, physicians can have a difficult time projecting how aggressive it will be.

Traditional methods used to predict outcomes, such as the Gleason grading system, have proved woefully inadequate, said Ronald A. DePinho, MD, study co-author and director of the Belfer Institute for Applied Cancer Science at Harvard Medical School's Dana-Farber Cancer Institute.

"Gleason grading has been used for about 45 years but only has a 60% to 75% predictability as to whether someone is going to go on to die of the disease," he said.

As a result, many men opt for aggressive treatments they don't need and that often lead to harmful side effects such as infertility and incontinence. For every life saved through such treatments, 48 men are treated unnecessarily, Dr. DePinho said. "There is a tremendous amount of overtreatment," he said.

Searching for accuracy

Attempts to find more accurate prediction methods through molecular analyses is complicated by the fact that it is difficult to find a molecular signature in most prostate cancers, Dr. DePinho said.

For the Nature study, published online Feb. 2, researchers took a more hypothetical approach. They used mouse models to better understand the genetic elements governing progression of the disease and tested those findings through analysis of 405 human tumor specimens from the Physicians' Health Study.

They identified the gene SMAD4 as a key suppressor of prostate tumor progression. They also examined the expression status of PTEN and SMAD4 and two SMAD4 target genes, SPP1 and cyclin D1, which control cancer cell invasion and proliferation.

The combination of loss of PTEN and SMAD4 and subsequent activation of SPP1 and cyclin D1 form a four-marker signature indicative of lethal metastasis in human prostate cancers.

Though the study yielded some exciting results, it is too soon to tell whether the four-gene signature will hold true for all aggressive prostate cancers, said Charles Saxe, PhD, program director of cancer cell biology and metastasis at the American Cancer Society.

Another study expected to appear soon in The Lancet is reported to identify 31 genes associated with prostate cancer progression, he said.

Both studies are making important strides in improving understanding of the mechanisms that cause cancer cells to be activated, Saxe said. "The four genes involved [in the Nature study] make a lot of sense based on what they are known to do relative to one another," he said.

Dr. DePinho said Metamark Genetics of Cambridge, Mass., is developing a test to identify the four genes that could be available to patients within the next year. Dr. DePinho founded the company with fellow study author Lynda Chin, MD.

The ultimate goal is to reduce costly and potentially harmful overtreatment of prostate cancer. "It's a huge advance in our ability to manage these men with prostate cancer," Dr. DePinho said.