Novel predictor markers of aggressiveness that outperform Gleason Score in prostate cancer

BIZZOTTO, JUAN; NEMIROVSKY, SERGIO; MAZZA, OSVALDO; VAZQUEZ, ELBA; VALACCO, PIA; LABANCA, ESTEFANIA; MITROFANOVA, ANTONINA; COTIGNOLA, JAVIER; LAGE-VICKERS, SOFIA; SANCHIS, PABLO; SCORTICATI, CARLOS; NAVONE, NORA; GUERON, GERALDINE

Encuentro; 27th Annual Virtual Scientific Retreat; 2020

Prostate Cancer Foundation

Prostate cancer (PCa) is the second most frequent cancer and the sixth leading cause of cancer-related death in men worldwide. Widespread use of prostate-specific antigen (PSA) levels for screening has led to a large increase in the incidence of diagnosed PCa and a reduction in both, the advanced disease and PCa mortality rates. However, the overtreatment of PCa is widely recognized. For men with newly diagnosed PCa, besides from stage, the strongest predictor of lethal PCa is the Gleason score (GS). PCa grading has significantly improved since Gleason?s original description in the mid-1960s. Literature reflects that, although some prostate cancers (PCas) are histo-pathologically grouped within the same Gleason Grade (GG), they can differ significantly in aggressiveness. In this work, we aimed at identifying molecular biomarkers that could improve risk prediction in PCa. In-depth proteomics analysis was performed on human PCa and Benign Prostatic Hyperplasia (BPH) tissues. We then validated the clinical significance of these peptides through an integrative bioinformatics analysis using public database repositories (32 datasets, n=5,974). We identified high expression of YWHAZ and NDRG1 to be strongly associated with poor PCa prognosis considering all Gleason scores. YWHAZ and NDRG1 expression defined two clearly and distinct subpopulations of patients with high and intermediate risk of disease progression. Adjusted multivariable analyses confirmed their independence from GS, patient age and TMPRSS2-ERG fusion. Further, ROC analysis unveiled that YWHAZ outperformed GS beyond 60 months post-diagnosis. In addition, the genomic landscape analysis of PCa patients with YWHAZ gene amplification, or increased mRNA and protein levels, revealed significant alterations in key DNA repair genes. We hereby state the relevance of YWHAZ in PCa, showcasing its role as an independent strong predictor of aggressiveness, making it a potential prognostic tool when taking into consideration the difficulties that PCa presents at the time of decision making.