Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer

Abstract

Background: The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables.

Methods: The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements.

Results: ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects.

Conclusions: A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor.

Impact: Interaction of PTEN and ERG pathways warrants further studies.

Figure 1

Kaplan–Meier analysis of progression-free survival of prostatectomy-treated patients according to (A) ERG, (B) AR, and (C) PTEN. D, ERG-positive patients with loss of PTEN expression had significantly shorter progression-free survival (P = 0.0085). E, PTEN expression had no significant effect on progression-free survival of ERG-negative patients (P = 0.5614). Mantel–Cox test was used to calculate the P values.

Figure 2

Kaplan–Meier analysis of progression-free survival of prostatectomy-treated patients according to (A) SPINK1 expression, and (B) TP53 deletion. Mantel–Cox test was used to calculate the P values.

Figure 3

Cumulative percentage of ERG positivity, high expression of AR, loss of PTEN, deletion of TP53 and 3p14, and strong SPINK1 staining in prostatectomy, locally recurrent CRPC, and CRPC metastasis specimens.