The days of uncertainty in diagnosing prostate cancer may be numbered. Howard Hughes Medical Institute (HHMI) scientists have developed a new, noninvasive test to help determine whether a man has prostate cancer. Further evaluation is planned to determine whether the diagnostic tool, which detects the presence of a cancer-causing fusion gene in men’s urine, could help clinicians reduce the number of prostate biopsies performed each year.

In the United States, more than one million men undergo prostate biopsies to test for cancer each year. The biopsies are usually recommended because of the level of prostate-specific antigen (PSA) in a man’s blood. PSA, a protein produced by prostate cells, is a marker of prostate growth. When a tumor is taking over the prostate, PSA levels are high. But PSA also increases when other conditions, such as benign prostatic hyperplasia, cause the prostate to become enlarged. So a high PSA level isn’t a surefire diagnosis of prostate cancer.

“Many more men have an elevated PSA than should need a biopsy.”
Arul M. Chinnaiyan

“Many more men have an elevated PSA than should need a biopsy,” says HHMI investigator Arul M. Chinnaiyan, who led the latest research.

In 2005, Chinnaiyan and his colleagues at the University of Michigan Medical School identified a fusion between two genes that’s present in around half of all prostate cancers. It’s called TMPRSS2:ERG. When the two genes, TMPRSS2 and ERG, combine, they drive prostate cells to grow out of control, leading to cancer. In studies since 2005, Chinnaiyan’s team has shown that TMPRSS2:ERG is highly specific for prostate cancer—it’s not found in normal prostate tissue, nor in any other kinds of cancer.

In their latest work, which is published in the August 3, 2011, issue of the journal Science Translational Medicine, the researchers measured the level of the fused gene in the urine of men with high PSA levels in their blood. Whether or not they found TMPRSS2:ERG, and how much of the gene fusion was detected, was a good indication of whether a man had prostate cancer.

“What it comes down to is that we have developed a new diagnostic test that helps identify which patients with elevated PSA levels require a biopsy for further workup,” says Chinnaiyan.

The study recruited 1,312 men at 12 different hospitals—a mix of academic research centers and community hospitals. All the men were already planning to have a prostate needle biopsy because of elevated PSA levels in the blood. The researchers collected the men’s urine before the biopsy and tested each sample for TMPRSS2:ERG. They then compared TMPRSS2:ERG levels in patients in which cancer was detected during biopsy to those in men whose biopsy was negative for cancer.

Around 50 percent of men who turned out to have prostate cancer tested positive for the fusion gene in their urine—consistent with previous work by Chinnaiyan. Fewer than five percent of men whose biopsy did not detect cancer had the gene present in their urine. While the lack of the fusion gene does not indicate that a man does not have prostate cancer, the most aggressive tumors were associated with presence of the gene.

“When you look at the test quantitatively, it gives you information in addition to simply detecting a tumor,” says Chinnaiyan. “The levels of the gene fusion correlate with whether a patient has clinically significant prostate cancer.” Higher levels of the fusion, he says, suggest a larger and more invasive prostate tumor.

When combined with PSA and another available urine test—for a gene called PCA3—the new test offers a way to stratify a patient’s risk of cancer. Those men with the highest levels of the gene should be given highest priority for biopsies, and ought to consider more thorough biopsies, says Chinnaiyan. Future versions of the test could provide even more information, he says.

“We think of this as the first generation version of this test,” says Chinnaiyan. “We hope to add to it in the future by testing for additional gene fusions that we know about.” The more cancer-causing genes are tested for, the more useful it will be as a screening test.

The diagnostic technology has been licensed by Gen-Probe, the company that developed the clinical grade assay for the latest test using Chinnaiyan’s findings. Gen-Probe is planning further clinical trials to evaluate the assay’s accuracy and specificity in diagnosing prostate cancer, and plans to submit the assay to the Food and Drug Administration for approval.