Enhancing risk stratification models in localized prostate cancer by novel validated tissue biomarkers.

Abstract

Background: Localized prostate cancer (PCa) is a largely heterogeneous disease regarding its clinical behavior. Current risk stratification relies on clinicopathological parameters and distinguishing between indolent and aggressive cases remains challenging. To improve risk stratification, we aimed to identify new prognostic markers for PCa.

Methods: We performed an in silico analysis on publicly available PCa transcriptome datasets. The top 20 prognostic genes were assessed in PCa tissue samples of our institutional cohort (n = 92) using the NanoString nCounter technology. The three most promising candidates were further assessed by immunohistochemistry (IHC) in an institutional (n = 121) and an independent validation cohort from the EMPACT consortium (n = 199). Cancer-specific survival (CSS) and progression-free survival (PFS) were used as endpoints.

Results: Our in silico analysis identified 113 prognostic genes. The prognostic values of seven of the top 20 genes were confirmed in our institutional radical prostatectomy (RPE) cohort. Low CENPO, P2RX5, ABCC5 as well as high ASF1B, NCAPH, UBE2C, and ZWINT gene expressions were associated with shorter CSS. IHC analysis confirmed the significant associations between NCAPH and UBE2C staining and worse CSS. In the external validation cohort, higher NCAPH and ZWINT protein expressions were associated with shorter PFS. The combination of the newly identified tissue protein markers improved standard risk stratification models, such as D'Amico, CAPRA, and Cambridge prognostic groups.

Conclusions: We identified and validated high tissue levels of NCAPH, UBE2C, and ZWINT as novel prognostic risk factors in clinically localized PCa patients. The use of these markers can improve routinely used risk estimation models.