Reduced AZGP1 expression is an independent predictor of early PSA recurrence and associated with ERG-fusion positive and PTEN deleted prostate cancers

Abstract

Zinc-alpha 2-glycoprotein (AZGP1) is involved in lipid metabolism and was suggested as a candidate prognostic biomarker in prostate cancer. To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, AZGP1 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and PTEN, 3p13, 5q21 and 6q15 deletions were available from earlier studies. AZGP1 expression was strong in benign prostatic glands but absent in 38.0% of 8,510 interpretable prostate cancers. Reduced AZGP1 expression was associated with TPMRSS2:ERG fusions, both by FISH and immunohistochemical analysis (p < 0.0001 each). For example, AZGP1 was absent in 54.6% of 2,029 ERG IHC positive but in only 28.1% of 2,398 ERG negative cancers. Irrespective of the ERG status, reduced AZGP1 expression was tightly linked to high Gleason score, advanced pathological tumor stage, positive nodal status and early PSA recurrence (p < 0.0001 each). Reduced AZGP1 expression was also strongly associated with PTEN deletions. AZGP1 immunostaining was lacking in 62.7% of 842 PTEN deleted but in only 37.3% of PTEN non-deleted cancers but retained strong prognostic influence in both subgroups (p < 0.0001 each). The prognostic role of AZGP1 expression was also independent of Gleason score, pT stage, pN stage, surgical margin status and preoperative PSA, irrespective of whether preoperative or postoperative variables were used for modeling. In conclusion, the results of our study demonstrate that reduced AZGP1 expression is strongly related to adverse prostate cancer prognosis, independently of established clinic-pathological variables and PTEN deletions. What's new? Zinc-binding Alpha-2-Glycoprotein 1 (AZGP1) is a secreted protein involved in lipid degradation and a putative prognostic marker in prostate cancer. Here the authors analyzed a tissue microarray containing more than 11,000 prostate cancer samples and found AZGP1 overall downregulated in cancers as compared to benign prostate tissue. Reduced AZGP1 expression was tightly linked to poor clinical outcome and was found in cancers harboring both fusions of the proto-oncogene ERG and deletions of the PTEN tumor suppressor gene. These results underscore the clinical potential of AZGP1 analysis in the care of prostate cancer patients.