Fusion Prostate Cancer: An Early Molecular Event Associated With Invasion

They say that the new gene, formed by the fusion of TMPRSS2 and ERG, may serve as a biomarker to separate patients who might benefit from radical prostate cancer therapy from those who potentially need little, if any, treatment.

"We believe this gene has the potential to be used as a diagnostic and prognostic test, which could offer thousands of patients peace of mind and spare them from unnecessary surgery and therapy," said the study's lead author, Sven Perner, M.D.,, a postdoctoral fellow in the Department of Pathology at Harvard University's Brigham and Women's Hospital in Boston. He worked with researchers from the Universities of California and Michigan, Johns Hopkins University and McGill University in Montreal.

Perner and his colleagues reported the discovery of the fused gene last year and they now say that TMPRSS2-ERG occurs in about 50 percent of prostate cancers - making it the most common genetic aberration in human cancer, and the first one found in a common solid cancer. Fused genes and chromosomal rearrangements have been found in several blood cancers, such as chronic myelogenous leukemia (CML) and in soft tissue tumors, such as Ewing's sarcoma, but these diseases are rare compared to prostate cancer, which is one of the leading cancers among American men.

In this study, the researchers sought to learn whether TMPRSS2-ERG is associated with a particular prostate cancer stage, and how it might be contributing to development of the cancer. They gathered 406 prostate tissue samples, representing a range of benign, precursor, and malignant prostate lesions, and used a FISH analysis to look for TMPRSS2-ERG. They didn't find any evidence of the fused gene in non-cancerous samples, but found it was present in 48.5 percent of localized prostate cancer tumors, 30 percent of hormone-naïve metastases, and in 33 percent of hormone refractory metastasis, as well as in about 20 percent of prostatic intraepithelial neoplasias, a lesion believed to be precursor of invasive prostate cancer.

The investigators also discovered that the gene fusion could occur in two different ways. The genes, TMPRSS2, which is regulated by the male sex-hormone androgen, and ERG, which is a potential oncogene, are located close to one another on chromosome 21. When fused, TMPRSS2 drives over-expression of the ERG gene. According to Perner, fusion can occur when the piece of DNA separating the genes breaks off and the genes merge (a process described as "fusion through deletion"), or if parts of each gene break off and switch positions ("translocation").

They found that TMPRSS2-ERG fusion through deletion was more common in the tumor samples as compared to TMPRSS2-ERG fusion through translocation. More recent work has found a significant association between TMPRSS2-ERG fusion and death from prostate cancer, although the researchers have not yet been able to determine which fusion form predicted the highest risk of death.

Perner says investigators are hoping to find a small molecule to inhibit the TMPRSS2-ERG fusion protein in the same way that the drug Gleevec has revolutionized care of CML.