Hidden in this molecular profile are answers to questions doctors hear every day: Is surgery really necessary? Can I afford to wait? Will the cancer come back?

Until now, physicians have been unable to decode these fingerprints. But a new study from the University of Michigan Medical School published in the Aug. 23 issue of Nature gives scientists their first look at the genetic and molecular profile of prostate cancer.

“The potential significance of this research is really in three areas -- diagnosis, prognosis and therapeutic,” says Mark Rubin, M.D., a co-author of the Nature paper and an associate professor of pathology and urology in the U-M Medical School. “The ultimate goal is to develop new tests that could help us identify the presence of prostate cancer and determine which patients have aggressive disease. Most importantly, we hope to identify new genes that we can target for therapy.”

Prostate cancer is the second leading cause of cancer deaths in men. Approximately one out of eight men will develop prostate cancer during his lifetime. Every year, about 40,000 American men die of the disease. Since there are usually no symptoms in the early stages when prostate cancer is most curable, researchers around the world have been searching for genetic markers for prostate cancer to help diagnose and treat the disease. Until now, there has been little progress.

In the new U-M study, Mark Rubin and colleagues at the U-M’s Comprehensive Cancer Center analyzed samples of prostate tissue from 50 men and found nearly 200 genes or gene fragments in which activity profiles varied consistently, depending on whether the tissue was normal or malignant.

U-M scientists then used DNA “chips” called microarrays to identify which genes were active in four types of tissue. These included normal prostate tissue from men with and without prostate cancer, tissue with benign changes, localized prostate cancer and aggressive, metastatic cancer.

Tissue samples were obtained from the U-M Prostate Specialized Program of Research Excellence (SPORE) tumor bank, funded by the National Cancer Institute and directed by study co-author Kenneth Pienta, M.D., a professor of internal medicine and surgery in the U-M Medical School.

“Microarray technology allows us to look at thousands of genes in prostate cells simultaneously,” says study co-author Arul Chinnaiyan, M.D., Ph.D., an assistant professor of pathology in the U-M Medical School. “This is important, because it is most likely that many genes are involved in the development and progression of prostate cancer – each controlling a different step in the process.”

While some of the genes identified in the U-M study are well known to cancer researchers, many others have never before been associated with prostate cancer. Two of these new genes are hepsin and pim-1, which could turn out to be important new clinical biomarkers for prostate cancer, according to Rubin.

When U-M scientists tested more than 700 prostate specimens for the presence of hepsin protein, the highest levels were found in pre-cancerous tissue –- the type seen just before prostate cancer develops, according to Chinnaiyan. Lowest levels were found in benign prostate tissue. While hepsin’s exact function is still unknown, U-M researchers suspect it plays a key role in establishment of tumors. Pim-1, a known cancer-causing gene, also was highly expressed in prostate cancer. Importantly, levels of both were correlated with patient prognosis.

According to Chinnaiyan, the next step is determining the functional role for each gene identified in the study as having an association with prostate cancer. “This paper will generate a great deal of work for researchers in many laboratories,” he predicts.

“It has been 15 years since the Prostate Specific Antigen (PSA) test became available in 1987,” adds Rubin. “Identifying the PSA level in your blood is useful, but it doesn’t tell you whether you have prostate cancer or not. This approach could give us many new diagnostic tests within three to five years. Eventually, it could lead to a diagnostic kit physicians could use to determine the best treatment and prognosis for their patients with prostate cancer.”

This research was supported by the National Cancer Institute’s Specialized Program of Research Excellence in Prostate Cancer. The U-M has applied for a patent on prostate cancer gene expression profiles for future diagnostic and therapeutic use.

Facts about prostate cancer

The prostate is a gland about the size of a walnut in the male reproductive system. It produces and stores seminal fluid, a milky fluid that nourishes sperm, which is released to form part of semen. The prostate surrounds the upper part of the urethra, the tube that empties urine from the bladder. If the prostate grows too large, the flow of urine can be slowed or stopped.

The risk of developing prostate cancer increases with age, with about 60 percent of cases diagnosed in men over age 60. Other risk factors include a family history of prostate cancer on either the mother’s or father’s side, and being of African-American ancestry.

All men over age 50 should have an annual prostate check-up, consisting of a digital rectal exam and a blood test to measure a protein called prostate-specific antigen or PSA. Men with additional risk factors should begin annual check-ups at age 40.

Both advanced prostate cancer and benign prostate enlargement can produce the same symptoms: weak or interrupted urine flow, inability or difficulty urinating, frequent urination, blood in the urine, painful or burning urination, painful ejaculation, continuing pain in the lower back, pelvis or upper thighs. - By Sally Pobojewski

Related websites:

U-M Health Topics A to Z: Prostate Cancer

National Cancer Institute’s CancerNet: Prostate Cancer

U-M Comprehensive Cancer Center

11-Sep-2001