Characterization of ETS gene aberrations in select histologic variants of prostate carcinoma

Histologic variants of prostate carcinoma account for 5-10% of the disease and are typically seen in association with conventional acinar carcinoma. These variants often differ from the latter in clinical, immunophenotypic, and biologic potential. Recently, recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factors ERG, ETV1, ETV4, or ETV5 have been identified in a majority of conventional prostate carcinomas. However, the frequency and significance of this critical molecular event is unknown in the histologic variants of prostate carcinoma. Here, we used break-apart fluorescence in situ hybridization to assess TMPRSS2 and ETS aberrations in a series of select histologic variants: foamy gland carcinoma (N=17), ductal adenocarcinoma (N=18), mucinous carcinoma (N=18), and small cell carcinoma (N=7). A histologic variation of acinar adenocarcinoma, demonstrating glomeruloid morphology (N=9), was also investigated. Overall, 55% of histologic variant or variation morphologies demonstrated ETS aberrations (ERG in 54% and ETV1 in 1%). TMPRSS2:ERG fusion was identified in 83% (15/18), 71% (5/7), 50% (9/18), 33% (3/9), and 29% (5/17) of mucinous, small cell, ductal, glomeruloid, and foamy gland prostate carcinomas, respectively. Previously, we reported that 100% of androgen-independent metastatic prostate carcinomas harboring TMPRSS2:ERG gene fusion were associated with interstitial deletion (Edel). Interestingly, ERG rearrangement in small cell carcinomas occurred exclusively through Edel, supporting the notion that TMPRSS2:ERG with Edel is an aggressive molecular subtype. SPINK1, a biomarker expressed exclusively in a subset of ETS negative prostate carcinomas, was expressed in 6% of ETS negative histologic variants, specifically in ductal adenocarcinoma. Notably, 88% (43/49) variant morphologies in this cohort showed concordance of TMPRSS2:ERG fusion with associated conventional acinar type, suggesting that variant morphology is clonally related to the latter. Overall, our data provide insight into the origin, molecular mechanism, and phenotypic association of ETS fusions in histologic variants of prostate carcinoma.