Metastatic prostate cancer molecular predictor identified

Prostate tumors that carry a "signature" of four molecular markers have the potential to become dangerously metastatic if not treated aggressively, according to a recent multicenter study.

Researchers say the discovery, published in Nature (2011; 470:269-73), lays the groundwork for the first gene-based test for determining whether a man's prostate cancer is likely to remain localized or spread.

By analyzing prostate cancer tissue from hundreds of men participating in a national health study, dozens of whom died of the disease, investigators led by Ronald DePinho, MD, of Dana-Farber Cancer Institute, Boston, found that the four-gene/protein signature more accurately predicted which patients would die from metastatic prostate cancer. The four-gene signature method alone was accurate 83% of the time. Combining the markers with the Gleason method produced an accuracy of approximately 90%.

Using computational biology techniques to analyze gene activity in mouse prostate cancer cells with inactive Pten gene, the team found pathways that seemed to play a constraining role. One, known as TGFβ-SMAD4, was particularly intriguing, as this pathway had been implicated in the metastasis of other tumor types in the past. When researchers conducted confirmatory molecular signaling studies to determine what happens when Pten is knocked out of commission, signaling in the TGFβ-SMAD4 pathway "shot through the roof," Dr. DePinho said, suggesting that the pathway had sprung into action.

When researchers generated mice whose prostate cells lacked both Pten and the Smad4 gene, the animals developed large, fast-growing tumors that spread to their lymph nodes and beyond. The team conducted a series of experiments to identify the genes most closely linked to the aggressive biology of prostate cancer. Among the hundreds of genes analyzed, two genes stood out: SPP1 and CyclinD1.

Dr. DePinho and colleagues reported that the four-gene signature-Pten, Smad4, SPP1, and CyclinD1-showed its effectiveness as a predictive tool for survival when researchers drew on data from the Physicians' Health Study. When the investigators screened prostate cancer samples from study participants for the four-gene/protein signature, it was more accurate in predicting the ultimate course of the illness than conventional methods were.

"By integrating a variety of techniques, we've identified a signature that has proven effective in distinguishing which men with prostate cancer are likely to progress and die from their disease and those who are not," Dr. DePinho said.