Clinical value of ERG, TFF3, and SPINK1 for molecular subtyping of prostate cancer

Abstract

BACKGROUND In view of the marked molecular heterogeneity of prostate cancer (PCa), clinical and pathologic parameters alone may be unreliable for predicting disease outcomes after surgical intervention. The development of biomarkers may be helpful to estimate tumor heterogeneity and stratify patients in terms of their risk of progression. Levels of v‐ets avian erythroblastosis virus E26 oncogene homolog (ERG), trefoil factor 3 (TFF3), and serine peptidase inhibitor, Kazal type 1 (SPINK1) are commonly elevated in PCa, but it is unclear whether the evaluation of these 3 markers can help to discriminate patients who will have different clinical outcomes. The authors investigated whether assessment of ERG, TFF3, and SPINK1 expression could help to define clinically relevant, distinct subsets of patients with PCa. METHODS The cohort consisted of 279 men with PCa who underwent radical prostatectomy at Henri Mondor Hospital. Expression levels of ERG, TFF3, and SPINK1 were evaluated immunohistochemically in the prostatectomy specimens. Potential associations of ERG, TFF3, and SPINK1 with age, prostate‐specific antigen (PSA), tumor stage, Gleason score, and biochemical recurrence, defined by PSA failure, were investigated. RESULTS Although prognostic significance was not observed for ERG or TFF3, an exclusive pattern of expression was demonstrated for TFF3 and ERG. SPINK1 expression was observed exclusively in a subgroup of cancers that expressed TFF3 (41 of 175 tumors). Moreover, SPINK1 positivity was identified as predictive of biochemical recurrence in univariate (P = .0009) and multivariate (P = .0003) analyses. CONCLUSIONS The current results suggest that ERG and TFF3 characterize 2 distinct subsets of PCa, with a more aggressive subgroup of TFF3‐expressing tumors that express SPINK1. Together, these findings support a rationale of screening for these biomarkers for prognostic purposes and molecular subtyping of the disease. Cancer 2015;121:1422–1430. © 2015 American Cancer Society.

High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer

“…Data published on the prognostic significance of ERG remains conflicting with some studies pointing toward worse outcome while others showing no association or even suggesting favorable prognosis. However, the preponderance of data seems to suggest that ERG has no prognostic value in localized disease, while being associated with a worse prognosis in cohorts not managed surgically (such as watchful waiting cohorts) [22,28,[41][42][43][44][45]. In a recent study, our group was the first to report a significant association between ERG expression and a higher-stage disease, but not with post-surgical PSA relapse in patients with localized cancer.…”

Overexpression of trefoil factor 3 (TFF3) contributes to the malignant progression in cervical cancer cells

“…Previous studies showed that overexpression of TFF3 promoted cell migration and invasion [6, 7, 11]. We next determined whether CDH1 mediated the effect of TFF3 on cell invasion in SiHa cells.…”

“…TFF3, behaved as an oncogene, promotes proliferation and invasion, improves survival, and increases oncogenicity in cancer cells, such as mammary carcinoma, gastric cancer and prostate carcinoma [5, 11]. TFF3 promoted epithelial tumorigenesis by inducing aberrant proliferation and inhibiting apoptosis [7].…”

Emerging Roles of SPINK1 in Cancer

“…Importantly, a majority of these studies reported SPINK1 overexpression mainly in androgen-induced E26 transformation-specific (ETS) gene fusion-negative tumors (31,32 ). In a recent study an inverse correlation between SPINK1 and trefoil factor 3 (TFF3) positivity and ETS negativity was shown, and in this TFF3 ϩ subgroup SPINK1 staining was associated with adverse clinical outcome (34 ). The findings that SPINK1 expression is confined to androgenindependent tumors and is higher in the metastases of castration-resistant prostate cancers than in primary tumors (32 ) suggest that SPINK1 may be involved in the metastatic processes.…”