Nuclear/cytoplasmic translocation of beta-Catenin protein is a strong predictor of unfavorable patient prognosis in ERG negative but not in ERG positive prostate cancer

beta-Catenin (CTNNB1) alterations are of potential interest as a prognostic feature and an option for therapeutic targeting in cancer. beta-Catenin (CTNNB1) is a dual function protein with roles in cell cohesion and gene transcription as a critical intracellular signal transducer in the Wnt signaling pathway. Cytoplasmic and nuclear translocation of the beta-Catenin protein results in an increased transcription of multiple cancer promoting genes. Aberrant nuclear beta-Catenin translocation is especially caused by loss of function mutations of genes encoding proteins of the beta-Catenin destruction complex or by gain of function mutations of CTNNB1. Affected cancers can be recognized by immunohistochemistry (IHC) due to their aberrant nuclear/cytoplasmic beta-Catenin staining. To study the prevalence and the potential role of aberrant beta-Catenin staining patterns, more than 6,000 adenocarcinomas of the prostate were analyzed by immunohistochemistry (IHC) in a tissue microarray format. All patients had been treated by radical prostatectomy. Clinical follow-up data were available for 4,895 patients. Among 6,114 evaluable cancers, membranous beta-Catenin staining was considered strong in 2,893 (47.3%), moderate in 2,737 (44.8%), and weak in 326 (5.3%) while additional 158 (2.6%) showed unequivocal nuclear/cytoplasmic translocation of beta-Catenin protein. Strong membranous beta-Catenin staining was more common in 1,926 tumors with (61.4%) than in 2,617 tumors without (37.7%) TMPRSS2:ERG fusion (p<0.0001). Strong membranous beta-Catenin staining was significantly associated with advanced pT stage as well as a high traditional (p<0.0001) and quantitative Gleason grade (p<0.0001). A comparison of beta-Catenin staining data with PSA recurrence revealed only minimal differences between tumors with weak, moderate, and strong membranous staining but a significantly increased risk for PSA recurrence for patients with nuclear/cytoplasmic beta-Catenin translocation (p=0.0448). A subgroup analysis of 1,258 ERG positive and 1,672 ERG negative cancers revealed that the unfavorable prognostic impact of nuclear/cytoplasmic beta-Catenin translocation was only seen in the ERG negative group (p<0.0001) while there was even a tendency towards better patient outcome in case of nuclear/cytoplasmic beta-Catenin translocation in ERG positive cancers. It is concluded that nuclear/cytoplasmic beta-Catenin translocation as detected by IHC is rare in prostate cancer and occurs in about 3% of patients. Only in ERG negative cancers, nuclear/cytoplasmic translocation of beta-Catenin is strongly linked to unfavorable disease course. The strong prognostic role of the beta-Catenin status could potentially be exploited for clinically relevant disease course prediction.