INTEGRATIVE TISSUE OMICS REVEAL PPP1R12B AND POSTN AS POTENTIAL PROGNOSTIC BIOMARKERS IN PROSTATE CANCER.

SABATER, AGUSTINA; PASCUAL, GASTON; GUERON, GERALDINE; BIZZOTTO, JUAN; SANCHIS, PABLO; VAZQUEZ, ELBA; LAVIGNOLLE, ROSARIO; SENIUK, ROCIO; COTIGNOLA, JAVIER

Conferencia; Prostate Cancer Foundation (PCF) Scientific Retreat 2021; 2022

Prostate Cancer Foundation (PCF)

Background: Formalin-fixed, paraffin-embedded (FFPE) tissues are highly valuable resources for translational high-throughput studies. Although it is well known that prostate cancer (PCa) is a progressive disease involving multiple gene alterations, little is known at the proteome level. The Gleason Grade (GG) is used as an aid for physicians to evaluate the prognosis of men with PCa using samples from prostate tissues. However, some PCas are histo-pathologically grouped within the same (GG) but can differ significantly in outcome. The aim of this study was to identify molecular biomarkers that can improve risk prediction of PCa with an eye toward those that could behave independently from GG and further clinical-pathological variables. Methods:An in-depth proteomic analysis (ESI-MS/MS) was performed on human prostate adenocarcinoma and benign prostate hyperplasia (BPH) tissues. Protein candidates enriched in PCa vs BPH were further evaluated in-silico using a custom-made pipeline for differential gene expression analysis and visualization across multiple publicly available datasets (7 PCa transcriptomic datasets, n = 875). Multivariable analyses were performed using clinical-pathological parameters as covariates, to validate potential biological makers.Results: Proteomic analysis yielded a list of 89 proteins enriched in PCa compared with BPH. Of those, 9 showed high expression in PCa datasets and a strong association with a poor prognosis. In particular PPP1R12B, FBLN5, CRIP2, and POSTN displayed associations with poor prognosis, independently from Gleason Score (GS), age and TMPRSS2-ERG fusion when performing a multivariable analysis (HR = 1.5, p = 0.0084; HR = 1.34, p = 0.035; HR = 1.36, p = 0.016 and HR = 1.4, p = 0.0028, respectively). Further, when considering a multivariable Cox-proportional hazard model including age, GS, TMPRSS2-ERG and the genes selected, only PPP1R12B (HR = 1.5, p = 0,013) and POSTN (HR = 1.3, p = 0.025) could be independent predictors of death risk. Conclusion:PPP1R12B and POSTN proteins were enriched in PCa human tissues and showed increased expression across multiple PCa transcriptomic datasets. Further, they appeared to be critical for overall survival in PCa patients and independent from known risk factors and predictors of PCa. Thus, these factors rise as potential prognostic markers.Funding acknowledgment: This work was supported by grants from Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (ANPCyT), Argentina: PICT-2016-0056, PICT-RAICES-2018-02639, and PICT-2019-2019-03215; and Universidad de Buenos Aires, Argentina: 20020170100585BA.Conflicts of Interest Disclosure Statement: The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data.