Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA

Urine TMPRSS2:ERG gene fusion could be used for stratification of patients at higher risk for prostate cancer. Old Gene Fusion, New Diagnostic Tricks The “PSA test” is a routine test for men over the age of 50 or for those at risk for prostate cancer. It measures the level of prostate-specific antigen (PSA) in the blood, and if that level is above a predefined cutoff, a biopsy is recommended for definitive diagnosis. This test is not perfect; benign conditions, such as an enlarged prostate, can contribute to high levels of PSA, resulting in a “false-positive” and subsequent overdiagnosis and overtreatment. Because of the high prevalence of prostate cancer (it is estimated that nearly 250,000 men will be diagnosed with the disease in 2011), it is clear that a more accurate test for prostate cancer is needed. Here, Tomlins et al. improve on the PSA test by taking a new twist on a known gene fusion, using it to stratify more than 1000 men in two multicenter cohorts based on risk for developing the disease. Recently, it was discovered that the fusion of two genes, the transmembrane protease, serine 2 (TMPRSS2) gene and the v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene, known as TMPRSS2:ERG, is overexpressed in more than 50% of PSA-screened prostate cancers. The protein product of this fusion cannot be detected in serum, so the authors decided to test for the presence of TMPRSS2:ERG mRNA in urine. First, they developed a clinical-grade, transcription-mediated amplification assay for quantifying fusion mRNA—this generated a TMPRSS2:ERG “score. ” Urine TMPRSS2:ERG score was linked to the presence of cancer, tumor volume, and clinically significant cancer in patients. Then, the authors combined the TMPRSS2:ERG score with the level of prostate cancer antigen 3 (PCA3) in urine. TMPRSS2:ERG+PCA3 improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator, thus demonstrating clinical utility. Who said you can’t teach an old gene fusion new tricks? By combining the cancer-specific fusion TMPRSS2:ERG score with levels of PSA (in serum) and PCA3 (in urine), Tomlins and colleagues demonstrated more accurate, individualized stratification of men at high risk for developing clinically significant prostate cancer—an important step in streamlining diagnosis and treatment. Moreover, men with extremes of TMPRSS2:ERG+PCA3 had different risks of cancer on biopsy; in combination with other clinicopathological features, urine TMPRSS2:ERG+PCA3 might also inform the urgency of biopsy after PSA screening. More than 1,000,000 men undergo prostate biopsy each year in the United States, most for “elevated” serum prostate-specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy.