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

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.

RNA‐based markers in biopsy cores with atypical small acinar proliferation: Predictive effect of T2E fusion positivity and MMP‐2 upregulation for a subsequent prostate cancer diagnosis

“…In a recent study, the association between T2E and AMACR, and a possible clinical effect of this association in localized PC were evaluated clinically and with in vitro experiments. 52 Similarly, our current results also show that the expression of AMACR was higher when T2E transcript was positive in ASAP-diagnosed cores. However, there is a need for in vitro studies to elucidate the relationship between higher AMACR expression and T2E fusion.…”

“…Moreover, in our study group, higher AMACR and AR expressions were associated with T2E fusion positivity. In a recent study, the association between T2E and AMACR , and a possible clinical effect of this association in localized PC were evaluated clinically and with in vitro experiments . Similarly, our current results also show that the expression of AMACR was higher when T2E transcript was positive in ASAP‐diagnosed cores.…”

A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy

“…Ki67 is a known marker of disease aggressiveness in prostate cancer (14). Increased AMACR staining has also been associated with most virulent oncogenic properties (15). However, in spite of higher mean values of these negative predictor markers, time-to-event analysis, albeit with short-term follow-up, showed no significant differences in the rates of PSA failure or use of adjuvant ADT or radiotherapy (Fig.…”

Emerging proteomics biomarkers and prostate cancer burden in Africa

“…For example, a recently described classification of the seven possible subtypes of PCa [28, 29] based on TMPRSS2: ERG translocations may represent a more useful molecular classification of PCa (in terms of therapeutic options) than histologic classification. Even though these emerging biomarkers (PCA3, TMPRSS2-ERG, and AMACR) have been validated in Western populations [30, 31], fewer such studies have primarily focused on African-American or African populations [32, 33]. A few other good reviews of genomic biomarkers of PCa can be found elsewhere [34–36].…”