Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer

Abstract

Background The TMPRSS2-ERG gene fusion is detected in approximately half of primary prostate cancers (PCa) yet the prognostic significance remains unclear. We hypothesized that ERG promotes the expression of common genes in primary PCa and metastatic castration-resistant PCa (CRPC), with the objective of identifying ERG-associated pathways, which may promote the transition from primary PCa to CRPC. Methods We constructed tissue microarrays (TMA) from 127 radical prostatectomy specimens, 20 LuCaP patient-derived xenografts (PDX), and 152 CRPC metastases obtained immediately at time of death. Nuclear ERG was assessed by immunohistochemistry (IHC). To characterize the molecular features of ERG-expressing PCa, a subset of IHC confirmed ERG+ or ERG-specimens including 11 radical prostatectomies, 20 LuCaP PDXs, and 45 CRPC metastases underwent gene expression analysis. Genes were ranked based on expression in primary PCa and CRPC. Common genes of interest were targeted for IHC analysis and expression compared with biochemical recurrence (BCR) status. Results IHC revealed that 43% of primary PCa, 35% of the LuCaP PDXs, and 18% of the CRPC metastases were ERG+ (12 of 48 patients [25%] had at least 1 ERG+ metastasis). Based on gene expression data and previous literature, two proteins involved in calcium signaling (NCALD, CACNA1D), a protein involved in inflammation (HLA-DMB), CD3 positive immune cells, and a novel ERG-associated protein, DCLK1 were evaluated in primary PCa and CRPC metastases. In ERG+ primary PCa, a weak association was seen with NCALD and CACNA1D protein expression. HLA-DMB expression and the presence of CD3 positive immune cells were decreased in CRPC metastases compared to primary PCa. DCLK1 was upregulated at the protein level in unpaired ERG+ primary PCa and CRPC metastases (p=0.0013 and p<0.0001, respectively). In primary PCa, ERG status or expression of targeted proteins was not associated with BCR-free survival. However for primary PCa, ERG+DCLK1+ patients exhibited shorter time to BCR (p=0.06) compared with ERG+DCLK1- patients. Conclusions This study examined ERG expression in primary PCa and CRPC. We have identified altered levels of inflammatory mediators associated with ERG expression. We determined expression of DCLK1 correlates with ERG expression and may play a role in primary PCa progression to metastatic CPRC.

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

“…To evaluate the prognostic significance of BROMO-10, first we used RNA-seq data from an independent cohort of PC from the Fred Hutchinson Cancer Research Center (Kumar et al, 2016; Roudier et al, 2016) (Figure 6E and F). Genes comprising the signature were deregulated in this cohort with 7 out of 10 genes being differentially expressed when comparing CRPCs to primary PCs.…”

“…( C ) Overlaps between overexpressed genes in CRPC in two clinical microarray datasets (Tables S4A and S4B), the genes associated with open chromatin sites in CRPC (Table S5) and the consensus genes downregulated by JQ1 treatment of two cell-lines (Table S2B) ( D ) 15 genes associated with open chromatin, overexpressed in CRPC and downregulated by JQ1 treatment. Underlined genes were also significant as assessed in Fred Hutchinson Cancer Research Centre (FHCRC) cohort comprising primary prostate cancers (PrCa; (Roudier et al, 2016)) and castration resistant PrCa (Kumar et al, 2016) ( E ) with indicated fold-change values and p values according to a two-sample t test ( F )…”

Corpora amylacea in prostatectomy tissue and associations with molecular, histological, and lifestyle factors

“…While this cross‐sectional study cannot tease apart temporality, these findings suggest that corpora amylacea formation may be a normal response to early cancers and the corpora amylacea may act to consolidate inflammatory debris to prevent more aggressive or mutated tumors; or perhaps the TMPRSS2:ERG fusion and aggressive tumors work to prevent the formation of corpora amylacea. Limited literature suggests that TMPRSS2:ERG fusion‐positive tumors are characterized by presence of inflammatory markers and that inflammation was associated with worse disease . TMPRSS2:ERG fusion‐positive tumors had higher IL‐6 expression than fusion‐negative tumors and the pro‐tumorigenic effects of the NF‐kB pathway were activated only in fusion‐positive cancer patients .…”

“…Limited literature suggests that TMPRSS2:ERG fusion-positive tumors are characterized by presence of inflammatory markers [30][31][32][33][34] and that inflammation was associated with worse disease. 4,5 TMPRSS2:ERG fusion-positive tumors had higher IL-6 expression than fusionnegative tumors 33 and the pro-tumorigenic effects of the NF-kB pathway were activated only in fusion-positive cancer patients.…”

Immunohistochemical staining of ERG and SOX9 as potential biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer

“…E26 transformation-specific (ETS)-related gene (ERG) expression was increased 30 to 80 times above normal levels in approximately 50% of prostate cancer [10, 11]. An in vitro study showed that overexpressed ERG binds to microtubules and alters their dynamics.…”