In situ expression of ERG protein in the context of tumor heterogeneity identifies prostate cancer patients with inferior prognosis

Prognostic biomarkers for prostate cancer are needed to improve prediction of disease course and guide treatment decisions. However, biomarker development is complicated by the common multifocality and heterogeneity of the disease. We aimed to determine the prognostic value of candidate biomarkers transcriptional regulator ERG and related ETS family genes, while considering tumor heterogeneity. In a multisampled, prospective, and treatment‐naïve radical prostatectomy cohort from one tertiary center (2010–2012, median follow‐up 8.1 years), we analyzed ERG protein (480 patients; 2047 tissue cores), and RNA of several ETS genes in a subcohort (165 patients; 778 fresh‐frozen tissue samples). Intra‐ and interfocal heterogeneity was identified in 29% and 33% (ERG protein) and 39% and 27% (ETS RNA) of patients, respectively. ERG protein and ETS RNA was identified exclusively in a nonindex tumor in 31% and 32% of patients, respectively. ERG protein demonstrated independent prognostic value in predicting biochemical (P = 0.04) and clinical recurrence (P = 0.004) and appeared to have greatest prognostic value for patients with Grade Groups 4–5. In conclusion, when heterogeneity is considered, ERG protein is a robust prognostic biomarker for prostate cancer. The prognostic relevance of the most common mutations in prostate cancer, involving ERG and other ETS genes, is still unclear. Utilizing a multisampled biobank, we show that ERG expression is heterogeneous both within and between malignant foci in the same patient. Despite significant heterogeneity, we find that ERG is a biomarker for poor prognosis for patients with localized prostate cancer.