Paired-sample Analysis of ERG Expression and TMPRSS2–ERG Fusion in Treatment-induced Neuroendocrine Prostate Cancer

Background/Aim: Prostate cancer is one of the most common malignancies in men. Although androgen deprivation therapy (ADT) offers substantial benefit, resistance to androgen signaling ultimately develops, leading to castration-resistant prostate cancer (CRPC). Approximately 10–17% of CRPC cases evolve into treatment-induced neuroendocrine prostate cancer (t-NEPC), an aggressive, androgen receptor (AR)–independent subtype. The TMPRSS2–ERG fusion gene is among the most frequent genomic alterations in prostate cancer; however, its involvement in t-NEPC development remains unclear.

Patients and Methods: We retrospectively analyzed nine Japanese cases of t-NEPC diagnosed across multiple institutions. Immunohistochemical staining for AR and ERG and RT-PCR for TMPRSS2–ERG fusion gene expression were performed on paired adenocarcinoma and t-NEPC samples. Clinical data – including prostate specific antigen levels, Gleason scores, metastatic patterns, and outcomes – were compared between ERG-positive and ERG-negative groups.

Results: ERG-positive prostate cancer was found in three of nine cases (33.3%), all of which were AR-positive, indicating that active AR signaling is required for TMPRSS2–ERG expression. ERG positivity was not clearly associated with prognosis or drug sensitivity, but time to NEPC differentiation tended to be shorter in ERG-positive cases. Only the e1e4 isoform of TMPRSS2–ERG was detected, while e2e4 was absent.

Conclusion: This study highlights heterogeneity in TMPRSS2–ERG fusion dynamics during t-NEPC evolution and suggests a potential association between ERG expression and earlier NE differentiation. This study provides a rare opportunity to analyze paired pre- and post-NEPC tissues, offering valuable insight into the relationship between ERG and TMPRSS2–ERG fusion gene expression and clinical parameters.