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High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer

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Tumor Biology

Abstract

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.

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Acknowledgments

This work was supported in part by the Prostate Cancer Foundation Young Investigator Award (T.A.B). This work was also supported by Prostate Cancer Canada and is proudly funded by the Movember Foundation (Grant #B2013-01).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada

    Adrian Box, Samar A. Hegazy & Tarek A. Bismar

  2. The Prostate Cancer Center, Calgary, Alberta, Canada

    Mohammed Alshalalfa, Samar A. Hegazy, Bryan Donnelly & Tarek A. Bismar

  3. Department of Urology, University of Calgary, Calgary, Alberta, Canada

    Bryan Donnelly

  4. Departments of Oncology, Biochemistry, and Molecular Biology, Calgary, Alberta, Canada

    Tarek A. Bismar

  5. Southern Alberta Cancer Institute and Tom Baker Cancer Center, Calgary, Alberta, Canada

    Tarek A. Bismar

  6. Faculty of Medicine, Departments of Pathology and Laboratory Medicine and Oncology, Rockyview General Hospital, University of Calgary, Calgary, Alberta, T2V 1P9, Canada

    Tarek A. Bismar

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Venn diagram of the differentially expressed genes with respect to ERG, AMACR or both. (JPG 63 kb)

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Functional protein network of the 152 genes specific to ERG and AMACR. (JPG 99 kb)

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Box, A., Alshalalfa, M., Hegazy, S.A. et al. High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer. Tumor Biol. 37, 12287–12299 (2016). https://doi.org/10.1007/s13277-016-5075-1

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