High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer.
Alpha-methylacyl-CoA racemase (AMACR) is a well-characterized marker extensively utilized in prostate cancer (PCA) diagnosis. However, the prognostic value of AMACR expression and its relation to TMPRSS2-ERG gene rearrangement as one of the most common molecular alterations in PCA is not fully explored. AMACR expression was investigated in a cohort of 218 men with localized PCA treated by radical prostatectomy and correlated with ERG and various clinical and pathological parameters. In vitro studies assessed AMACR changes to ERG knockdown and other related genes. In addition, bioinformatics validated the significance of AMACR/ERG expression and assessed relevant genetic signatures in relation to AMACR/ERG expression. AMACR expression was significantly associated with disease progression and with ERG (p ∼0). Seventeen percent of cancer foci showed negative/weak AMACR expression while being ERG positive. High AMACR expression was significantly associated with positive surgical margins (p = 0.01), specifically in tumors with lower Gleason score <7, with ∼95 % exhibiting positive surgical margin (p = 0.008). High AMACR showed marginal association with PSA biochemical recurrence (BCR) (p = 0.06) which was slightly more pronounced in ERG-positive tumors (p = 0.04). This was validated in other public cohorts. However, in this cohort, the association with BCR was not statistically significant in multivariate analysis (p = 0.09). Using in vitro cellular models, AMACR messenger RNA (mRNA) expression, but not protein levels, showed an association with ERG expression. We report for the first time a significant association between AMACR and ERG with prognostic implication. Patients with high AMACR/ERG-positive PCA may be at higher risk for disease progression, and additional studies in larger cohorts are needed to confirm the above findings. Functional studies investigating the molecular pathways connecting AMACR and ERG may provide an additional insight into PCA progression pathways.
Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada.
Adrian
A
Box
The Prostate Cancer Center, Calgary, Alberta, Canada.
Mohammed
M
Alshalalfa
Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada.|The Prostate Cancer Center, Calgary, Alberta, Canada.
Samar A
SA
Hegazy
The Prostate Cancer Center, Calgary, Alberta, Canada.|Department of Urology, University of Calgary, Calgary, Alberta, Canada.
Bryan
B
Donnelly
Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada. tarek.bismar@cls.ab.ca.|The Prostate Cancer Center, Calgary, Alberta, Canada. tarek.bismar@cls.ab.ca.|Departments of Oncology, Biochemistry, and Molecular Biology, Calgary, Alberta, Canada. tarek.bismar@cls.ab.ca.|Southern Alberta Cancer Institute and Tom Baker Cancer Center, Calgary, Alberta, Canada. tarek.bismar@cls.ab.ca.|Faculty of Medicine, Departments of Pathology and Laboratory Medicine and Oncology, Rockyview General Hospital, University of Calgary, Calgary, Alberta, T2V 1P9, Canada. tarek.bismar@cls.ab.ca.
Tarek A
TA
Bismar
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D034622:RNA Interference; D019998:Racemases and Epimerases / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071230:Transcriptional Regulator ERG / Q000096:biosynthesis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D000071230:Transcriptional Regulator ERG; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase
AMACR; Biochemical recurrence; Biomarkers; Disease progression; ERG; PSA relapse; Prognosis; Surgical margin