Discovery
January 25, 2016

When the cat's away, the mice will play. That's what's happening, on a very tiny scale, in aggressive prostate cancer, and it's being demonstrated in important work by urologic pathologists Tamara Lotan, M.D., Angelo M. De Marzo, M.D., Ph.D., and colleagues. "Two of the most common genetic changes that we see in aggressive prostate cancer are the loss of the PTEN gene and rearrangements that lead to over-expression of an oncogene called ERG," says Lotan.

In this case, the cat — the keeper of the peace — is a gene called PTEN. PTEN is a tumor suppressor. Its job is to put the brakes on the out-of-control growth that leads to cancer. Without the restraint of PTEN — the gene is knocked out in about half of lethal prostate tumors — cancer cells start behaving badly. Previously in Discovery, we reported that PTEN is one of the few genes whose loss has been consistently associated with aggressive prostate cancer. Two years ago, Lotan, De Marzo, and others at Hopkins found a strong correlation between the loss of PTEN and the signs of aggressive prostate cancer, including the Gleason grade of the tumor as well as the stage of the tumor and the time it took for metastases to develop; this work was published in Clinical Cancer Research. In a larger follow-up study just published in European Urology Focus by Lotan's team, the scientists found that PTEN loss correlated with faster recurrences after radical prostatectomy.

ERG, on the other hand, is a troublemaker, a gene that may promote the growth of cancer. With PTEN out of the picture, it stars in its own episode of "genes gone wild." Lotan's team has worked with De Marzo and other Johns Hopkins investigators to develop and test simple, inexpensive assays that show the status of PTEN and ERG in prostate tumors. In work recently published in Modern Pathology, Lotan and colleagues showed that men who have Gleason 6 tumors with PTEN loss are about three times more likely to be upgraded to Gleason 7 or higher at radical prostatectomy. Further, Lotan's team showed that prostate tumors with PTEN loss are two to three times more likely to be lethal compared to tumors without PTEN loss, "even after adjusting for the usual clinical and pathologic signs we currently use to predict prognosis," Lotan says. "Interestingly, PTEN loss is more tightly associated with lethal disease when the tumor does not have ERG gene rearrangement – suggesting a significant interaction between these important genes in the progression of prostate cancer." Lotan recently presented these findings at meetings of the United States and Canadian Academy of Pathology, and of the American Association for Cancer Research.

Validated tests developed by Lotan, De Marzo and colleagues are now being offered in the clinical lab at Johns Hopkins, and Lotan's team is working with investigators from several other academic centers to develop these tests into FDA-cleared prognostic and predictive biomarkers.