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

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

Congreso; Prostate Cancer Foundation Scientific Retreat 2020; 2020

Prostate cancer (PCa) is the second most frequent cancer and the sixth leadingcause of cancer-related death in men worldwide. Widespread use of prostate-specific antigen (PSA) levels for screening has led to a large increase in theincidence of diagnosed PCa and a reduction in both, the advanced disease and PCamortality rates. However, the overtreatment of PCa is widely recognized. For menwith newly diagnosed PCa, besides from stage, the strongest predictor of lethal PCais the Gleason score (GS). PCa grading has significantly improved since Gleason?soriginal description in the mid-1960s. Literature reflects that, although some prostatecancers (PCas) are histo-pathologically grouped within the same Gleason Grade(GG), they can differ significantly in aggressiveness. In this work, we aimed atidentifying molecular biomarkers that could improve risk prediction in PCa. In-depthproteomics analysis was performed on human PCa and Benign ProstaticHyperplasia (BPH) tissues. We then validated the clinical significance of thesepeptides through an integrative bioinformatics analysis using public databaserepositories (32 datasets, n=5,974).We identified high expression of YWHAZ and NDRG1 to be strongly associated withpoor PCa prognosis considering all Gleason scores. YWHAZ and NDRG1expression defined two clearly and distinct subpopulations of patients with high andintermediate risk of disease progression. Adjusted multivariable analyses confirmedtheir independence from GS, patient age and TMPRSS2-ERG fusion. Further, ROCanalysis unveiled that YWHAZ outperformed GS beyond 60 months post-diagnosis.In addition, the genomic landscape analysis of PCa patients with YWHAZ geneamplification, or increased mRNA and protein levels, revealed significant alterationsin key DNA repair genes.We hereby state the relevance of YWHAZ in PCa, showcasing its role as anindependent strong predictor of aggressiveness, making it a potential prognostic toolwhen taking into consideration the difficulties that PCa presents at the time ofdecision making.