Abstract
BACKGROUND: ETS2 expression in prostate cancer (PCa) shows variability, with overexpression and loss reported. ETS2 can be dysregulated through proteasomal degradation, but p53 missense mutants may stabilize ETS2 by preventing this process. TP53 mutations are more frequent in metastatic PCa, and their identification in primary tumors could serve as an early marker for patient stratification. In addition, TMPRSS2-ERG fusion often arises from an intrachromosomal deletion including ETS2 locus.
METHODS AND RESULTS: ETS2, p53 and ERG protein expression were assessed by immunohistochemistry in a surgically treated PCa patients' cohort (N = 199). ETS2 and TMPRRS2-ERG mRNA were evaluated by qPCR in an independent series (N = 80). Relationship between molecular markers, and with clinicopathological characteristics was analyzed. High ETS2 protein expression was observed in 34.7% of tumors. Aberrant p53 immunostaining was detected in 5.5% of cases, being associated with high ETS2 expression (p = 0.050). p53 positivity was related to GG5 (p = 0.007) and unifocality (p = 0.011). Shorter time to PSA recurrence was observed in p53-positive patients (p = 0.002). Cases with high ETS2 expression but negative p53 staining had the longest time to recurrence, whereas p53-positive cases, regardless of ETS2, had the shortest (p = 0.002). ERG protein expression -surrogate marker of TMPRSS2-ERG- was strongly associated with high ETS2 (p < 0.001). At mRNA level, low ETS2 expression correlated with TMPRSS2-ERG fusion (p = 0.018), and showed a trend toward association with intrachromosomal deletion (p = 0.113) and high-stage (p = 0.054).
CONCLUSIONS: In conclusion, p53 staining was consistently associated with aggressive PCa and may serve as a reliable prognostic marker. High ETS2 expression correlates with delayed PSA recurrence in p53-negative tumors.