A First-Generation Multiplex Biomarker Analysis of Urine for the Early Detection of Prostate Cancer

Abstract

Although prostate-specific antigen (PSA) serum level is currently the standard of care for prostate cancer screening in the United States, it lacks ideal specificity and additional biomarkers are needed to supplement or potentially replace serum PSA testing. Emerging evidence suggests that monitoring the noncoding RNA transcript PCA3 in urine may be useful in detecting prostate cancer in patients with elevated PSA levels. Here, we show that a multiplex panel of urine transcripts outperforms PCA3 transcript alone for the detection of prostate cancer. We measured the expression of seven putative prostate cancer biomarkers, including PCA3, in sedimented urine using quantitative PCR on a cohort of 234 patients presenting for biopsy or radical prostatectomy. By univariate analysis, we found that increased GOLPH2, SPINK1, and PCA3 transcript expression and TMPRSS2:ERG fusion status were significant predictors of prostate cancer. Multivariate regression analysis showed that a multiplexed model, including these biomarkers, outperformed serum PSA or PCA3 alone in detecting prostate cancer. The area under the receiver-operating characteristic curve was 0.758 for the multiplexed model versus 0.662 for PCA3 alone (P = 0.003). The sensitivity and specificity for the multiplexed model were 65.9% and 76.0%, respectively, and the positive and negative predictive values were 79.8% and 60.8%, respectively. Taken together, these results provide the framework for the development of highly optimized, multiplex urine biomarker tests for more accurate detection of prostate cancer. [Cancer Res 2008;68(3):645-9]

ETS rearrangements in prostate cancer

“…Several studies to date have demonstrated the detection of the TMPRSS2:ERG fusion transcripts in urine. 44,45,67 These studies, and other unpublished reports, demonstrate a high specificity. Unlike PSA, which can be elevated in benign conditions as well as cancer, the presence of TMPRSS2:ERG transcripts has only been reported in neoplastic cells.…”

Urine markers in monitoring for prostate cancer

“…11 On the other hand, AMACR transcripts normalized to PSA were not statistically significant predictors of CaP in a recent multiplex study of urine markers (see below). 12 GSTP1 (glutathione S-transferase P1) belongs to a family of enzymes involved in protecting DNA from free radicals. CaP is associated with the loss of GSTP1 expression due to promoter hypermethylation.…”

“…Current biopsy strategies may miss heterogenous tumor foci, and urine-based assay would have a great advantage because the cells from multiple cancerous foci of whole prostate could be released and collected. 69 Laxman et al 12 reported that a multiplex panel of urine transcripts outperforms PCA3 transcript and serum PSA alone in detecting CaP. Expression of seven putative prostate cancer biomarkers was measured (PCA3, PSA, GOLPH2, SPINK1, AMACR, TMPRSS2/ERG, TFF3) by qRT-PCR in urine samples.…”

“…Expression of seven putative prostate cancer biomarkers was measured (PCA3, PSA, GOLPH2, SPINK1, AMACR, TMPRSS2/ERG, TFF3) by qRT-PCR in urine samples. 12 They showed that increased GOLPH2 (Golgi phosphoprotein 2), SPINK1 (serine peptidase inhibitor, Kasal type 1), PCA3 transcript expression and TMPRSS2/ERG fusion status were significant predictors of CaP (sensitivity 66% and specificity 76%). 12 Improved sensitivity to detect CaP has also been reported for combined detection of TMPRSS2/ERG and PCA3 transcripts in urine on a sample of patients with serum PSA X3 ng ml À1 and/or an abnormal DRE.…”

“…12 They showed that increased GOLPH2 (Golgi phosphoprotein 2), SPINK1 (serine peptidase inhibitor, Kasal type 1), PCA3 transcript expression and TMPRSS2/ERG fusion status were significant predictors of CaP (sensitivity 66% and specificity 76%). 12 Improved sensitivity to detect CaP has also been reported for combined detection of TMPRSS2/ERG and PCA3 transcripts in urine on a sample of patients with serum PSA X3 ng ml À1 and/or an abnormal DRE. 73 Separate sensitivities for detecting TMPRSS2/ERG fusion and PCA3 transcripts in the urine were 37 and 62%, respectively, but by combining both markers the sensitivity increased to 73%.…”