Prostatic carcinoma with neuroendocrine differentiation harboring the EWSR1-FEV fusion transcript in a man with the WRN G327X germline mutation: A new variant of prostatic carcinoma or a member of the Ewing sarcoma family of tumors?

Abstract

Since the discovery of the TMPRSS2-ERG fusion transcript in prostatic carcinoma (PCa) more than ten years ago, a long list of recurrent genomic rearrangements involving other transcription factors of the ETS family has been described. Fusions of ETS with the EWSR1 partner gene define many members of the Ewing family of tumors, including primitive neuroectodermal tumor (PNET). Although the expression of EWSR1 appears to be necessary for the oncogenic effects of ETS factors, the EWSR1-ETS rearrangement has never been reported in PCa. Herein, we discuss the pathologic diagnosis of a prostatic tumor in a 44 year-old man, recently treated with finasteride, with the EWSR1-FEV fusion (exon 7: exon 2, join in-frame) discovered by RNA-sequencing and fluorescence in situ hybridization. The tumor was morphologically and immunophenotypically equivocal for a Ewing sarcoma/PNET, and most consistent with a PCa with neuroendocrine differentiation. The patient's family history of PCa led to germline mutation testing by next-generation sequencing showing heterozygosity for the WRN^G327X mutation. The WRN protein along with ATM, BRCA1, BRCA2, and RAD51 among others, comprise a DNA repair system by homologous recombination, and its alterations are associated with forms of hereditary PCa. We dispute whether the detection of EWSR1-FEV mandates one to diagnose the patient's tumor as a member of the Ewing sarcoma family.

Keywords: EWSR1; Fluorescence in situ hybridization; Gene fusion; Next-generation sequencing; Primitive neuroectodermal tumors; Prostate cancer.