Researchers conducted an elaborate series of experiments to identify the genes most closely linked to the aggressive biology of prostate cancer. They found about 300 genes that distinguished the two groups – indolent versus aggressive prostate cancers.
Prostate tumors that carry a “signature” of four molecular markers have the potential to become dangerously metastatic if not treated aggressively, researchers at Dana-Farber Cancer Institute report in a study published by the journal Nature.
The discovery lays the groundwork for the first gene-based test for determining whether a man’s prostate cancer is likely to remain dormant within the prostate gland, or spread lethally to other parts of the body.
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, Lynda Chin, MD, and Zhihu Ding, PhD, of Dana-Farber, in collaboration with Massimo Loda, MD, of Dana-Farber and Brigham and Women’s Hospital, and Lorelei Mucci, PhD, of Brigham and Women’s and Harvard School of Public Health, found that the four-gene/protein signature more accurately predicted which patients would die from metastatic spread than did the conventional method.
The standard measure of prostate cancer’s aggressiveness, known as the Gleason score (which is based on cancer cells’ appearance under a microscope), is accurate about 60 to 70 percent of the time depending on the skill of the pathologist. The four-gene signature method alone was accurate 83 percent of the time. Combining the markers and Gleason methods produced an accuracy of approximately 90 percent.
“It’s widely recognized that many prostate cancer patients are treated unnecessarily,” says DePinho, who is the director of Dana-Farber’s Belfer Institute for Applied Cancer Science. “The vast majority of prostate cancers would not become life-threatening, even if left untreated. But because we can’t accurately forecast which are likely to spread and which aren’t, there is a tendency to unnecessarily subject many men to draconian interventions.”
The main obstacle to developing better prognostic tests for prostate cancer has been the lack of uniformity of cells in different tumors, and even within a single tumor.
In the current study, researchers began with the well-established fact that prostate cancers without a working copy of the Pten gene tend to remain fairly idle and don’t trespass beyond the prostate gland itself. Researchers theorized that the loss of Pten in turn activates a collection of genes ? a pathway ? functioning to constrain the tumor’s growth and invasion. If that pathway was shut down, they reasoned, the tumor would begin to break loose from the prostate and spread insidiously through the body.
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, which has been tracking the health of thousands of U.S. physicians for nearly 30 years.
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 ? computational biology, genetically engineered model systems, molecular and cellular biology, and human tissue microarrays ? 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,” DePinho remarks.
Efforts are already underway to use this knowledge to develop a clinical test ? which we hope will occur within a year or so ? that will enable doctors and patients to make more accurate treatment decisions and avoid unnecessary aggressive interventions which adversely impact on quality of life and deplete over-extended healthcare resources. This science holds potential to illuminate a long-sought answer for optimal management of this complex disease.
Source: Dana-Farber Cancer Institute, USA