Integrative tissue ?omics? reveals a biomarker gene signature that re-defines prostate cancer risk for Gleason Score 6 & 7

LAGE VICKERS, SOFIA; BIZZOTO, JUAN; VALACCO PIA; NEMIROVSKY SERGIO; LABANCA ESTEFANIA; SCORTICATI CARLOS; MAZZA OSVALDO; NAVONE NORA; ELBA VAZQUEZ; COTIGNOLA, JAVIER; GUERON GERALDINE

Congreso; Prostate Cancer Foundation Annual Retreat; 2019

ABSTRACTBackground: It is well known that prostate cancer (PCa) is a progressive disease involving multiple genealterations. Gleason score (GS) is a morphologic feature of PCa used to evaluate the risk of diseaseprogression. However, GS often fail to clearly distinguish between indolent and aggressive disease. Theaim of this study was to identify potential biomarkers for PCa risk stratification.Methods: An in-depth proteomics analysis (LC ESI-MS/MS) was performed on human PCa and BPHtissues. First, we identified differentially expressed proteins between PCa and BPH samples. We thenfiltered the proteins based on peptide spectrum matches and selected a panel of candidates. To assessand validate the clinical significance of these peptides we performed an integrative bioinformatics analysisusing public database repositories.Results: Here, we identified 14-3-3ζ/δ, an androgen receptor downstream target, as one of the proteinsenriched in PCa compared with BPH. We identified high expression of 14-3-3ζ/δ to be strongly associatedwith poor prognosis across different PCa datasets (HR=3.07, P˂0.001 for the GSE16560 dataset;HR=3.94, P˂0.001 for the GSE70769 dataset). Further, multivariate analyses displayed high significantcorrelation with poor prognosis, independent from GS, age, PSA at diagnosis and TMPRSS2-ERG fusion(HR=2.21, P˂0.001 for the GSE16560 dataset; HR=2.32, P=0.01 for the GSE70769 dataset). Next, wefocused on the expression of YWHAZ (14-3-3ζ/δ encoding gene) in men with GS 7 to identify itspotentiality as a predictor of unfavorable outcome. Results show that high expression of YWHAZ in theGS 7 (3+4) and (4+3) subgroups significantly correlated with decreased overall survival (HR=2.04,P=0.027 and HR=2.32, P=0.05, respectively). Further we re-screened the enriched PCa genes for GS 6-7(3+4) and found a potential biomarker gene signature for risk stratification in low-intermediate GS.Patients with co-occurrent gene dysregulation of GDF15, APOE, NDRG1 and YWHAZ were significantlyassociated with poor clinical outcome (overall survival HR=1.6, P