Absence of KLK4-KLKP1 Fusion Corroborate with PTEN Loss in Characterizing Men at Higher Risk for Biochemical Recurrence in Middle Eastern Prostate Cancer Cohort

Abstract

Background: KLK4-KLKP1 fusion is a recently described molecular event in prostate cancer (PCa). This new biomarker has not been characterized in the Middle Eastern (ME) population. Objective: We assessed the incidence, characterization, and prognostic value of KLK4-KLKP1 fusion in a ME cohort of men with PCa and assessed the relationship of this marker to commonly known biomarkers (PTEN, ERG, SPINK1). Design, setting and participants: We interrogated a cohort of ME men with localized PCa treated by radical prostatectomy between 2005 and 2015 (n=340). KLK4-KLKP1 fusion status was assessed by RNA Chromogenic in situ hybridization (CISH) and correlated to pathological and clinical parameters.Outcome measurements and statistical analysis: RNA-CISH expression of KLK4-KLKP1 was correlated with prognostic factors, ERG, PTEN and SPINK1 expression and with biochemical recurrence (BCR) post radical prostatectomy.Results and limitations: 51.7% of patients’ samples were positive for KLK4-KLKP1; with the expression more commonly found in cores of PCa (38%) versus non-cancer (20.6%) (p <0.0001) and in lower Gleason Grade Group tumors (1-3) vs (4-5). KLK4-KLKP1 positivity was associated with ERG positivity and inversely associated with PTEN loss. No association was noticed with SPINK1 expression, seminal vesicle invasion, positive surgical margin, pathological stage, or patient age (<50 or ³ 50). When correlating to BCR, only PTEN loss was associated with BCR, and this effect became more pronounced when combined with KLK4-KLKP1 negativity (HR: 2.31, CI: 1.03-5.20, p=0.042). Conclusions: KLK4-KLKP1 expression is more common in ME vs North American (NA) populations. It is associated with ERG positivity and inversely with PTEN loss. KLK4-KLKP1 positivity showed no association with any clinical or pathological parameters, however, it demonstrated a somewhat protective effect when combined with PTEN status. Patient Summary: KLK4-KLKP1 is a newly discovered biomarker expressed in PCa with a higher incidence in the ME population. KLK4-KLKP1 positivity is associated with certain molecular subtypes (ERG-positive, PTEN intact).