Four-Gene Signature Predicts Prostate Cancer Prognosis

A gene-based test determines whether prostate cancer is likely to remain dormant within the prostate gland, or spread lethally to other parts of the body.

In 85% of prostate cancer cases, the prostate gland holds more than one tumor focus, each of which may contain a different assortment of malignant cells with a distinct set of gene abnormalities. Such diversity makes it difficult to identify genes or other features that reliably indicate a tumor's potential to spread.

A multi-institute collaborative study, led by scientists at the Dana-Farber Cancer Institute, (Boston, MA, USA), have analyzed prostate cancer tissue from hundreds of men participating in a national health study, dozens of whom died of the disease. They performed immunohistochemical staining with validated antibodies against four genes on a tumor tissue microarrays (TMA) comprising a cohort of 405 tumor specimens randomly selected from men diagnosed with prostate cancer who underwent radical prostatectomy. The four genes encoded for the following proteins: the phosphatase and tensin homologue (PTEN), a homologue of the Drosophila "mothers against decapentaplegic" (SMAD4), a cell cycle regulator (cyclin D1), and secreted phosphoprotein 1 (SPP1). Other techniques and a mouse model were used to validate the findings.

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 US 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. They conducted an elaborate series of experiments to identify the genes most closely linked to the aggressive biology of prostate cancer. Among the hundreds of genes analyzed, two such genes stood out: SPP1 and CyclinD1, both of which, intriguingly, are close working partners of Smad4.

Ronald DePinho, MD, a lead author of the study, said. "By integrating a variety of techniques, computational biology, genetically engineered model systems, molecular and cellular biology, and human tissue microarrays, we have 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". The study was published on February 2, 2011in the journal Nature.

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Dana-Farber Cancer Institute