Multiplex biomarker approach for determining risk of prostate-specific antigen-defined recurrence of prostate cancer.
BACKGROUND
Molecular signatures in cancer tissue may be useful for diagnosis and are associated with survival. We used results from high-density tissue microarrays (TMAs) to define combinations of candidate biomarkers associated with the rate of prostate cancer progression after radical prostatectomy that could identify patients at high risk for recurrence.


METHODS
Fourteen candidate biomarkers for prostate cancer for which antibodies are available included hepsin, pim-1 kinase, E-cadherin (ECAD; cell adhesion molecule), alpha-methylacyl-coenzyme A racemase, and EZH2 (enhancer of zeste homolog 2, a transcriptional repressor). TMAs containing more than 2000 tumor samples from 259 patients who underwent radical prostatectomy for localized prostate cancer were studied with these antibodies. Immunohistochemistry results were evaluated in conjunction with clinical parameters associated with prostate cancer progression, including tumor stage, Gleason score, and prostate-specific antigen (PSA) level. Recurrence was defined as a postsurgery PSA level of more than 0.2 ng/mL. All statistical tests were two-sided.


RESULTS
Moderate or strong expression of EZH2 coupled with at most moderate expression of ECAD (i.e., a positive EZH2:ECAD status) was the biomarker combination that was most strongly associated with the recurrence of prostate cancer. EZH2:ECAD status was statistically significantly associated with prostate cancer recurrence in a training set of 103 patients (relative risk [RR] = 2.52, 95% confidence interval [CI] = 1.09 to 5.81; P =.021), in a validation set of 80 patients (RR = 3.72, 95% CI = 1.27 to 10.91; P =.009), and in the combined set of 183 patients (RR = 2.96, 95% CI = 1.56 to 5.61; P<.001). EZH2:ECAD status was statistically significantly associated with disease recurrence even after adjusting for clinical parameters, such as tumor stage, Gleason score, and PSA level (hazard ratio = 3.19, 95% CI = 1.50 to 6.77; P =.003).


CONCLUSIONS
EZH2:ECAD status was statistically significantly associated with prostate cancer recurrence after radical prostatectomy and may be useful in defining a cohort of high-risk patients.
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Daniel R
DR
Rhodes
Martin G
MG
Sanda
Arie P
AP
Otte
Arul M
AM
Chinnaiyan
Mark A
MA
Rubin
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D015820:Cadherins / Q000032:analysis; D018450:Disease Progression; D029721:Drosophila Proteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis; D016017:Odds Ratio; D063151:Polycomb Repressive Complex 2; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000032:analysis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000175:diagnosis* / Q000473:pathology / Q000601:surgery; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051573:Proto-Oncogene Proteins c-pim-1; D019998:Racemases and Epimerases / Q000032:analysis; D012097:Repressor Proteins / Q000032:analysis; D018570:Risk Assessment; D012697:Serine Endopeptidases / Q000032:analysis
D014408:Biomarkers, Tumor; D015820:Cadherins; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C083329:E(z) protein, Drosophila; D063151:Polycomb Repressive Complex 2; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D012697:Serine Endopeptidases; C055645:hepsin; D017430:Prostate-Specific Antigen; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase