Correspondence DOT1L-HES6 fusion drives androgen independent growth in prostate cancer

M olecular therapies targeting theandrogen receptor (AR) or path-ways involved in androgen synthesis form a critical component of the standard-of-care in treating aggressive, non-localized prostate cancers. The major prob-lem with these therapies is that castration resistant clones arise within 1–3 years of treatment initiation, leading to clinical relapse and eventual death. Previously reported mechanisms of castration resis-tance include amplification and mutation of AR (Taplin et al, 1995; Visakorpi et al, 1995), neuroendocrine differentiation (Beltran et al, 2011), and aberrant activation of the glucocorticoid receptor (Arora et al, 2013). In a previous issue of this journal, Ramos-Montoya et al, 2014 implicated the tran-scription factor HES6 as another important player in the induction of castration resis-tance. In this correspondence, we present further evidence for the role of HES6 in castration resistant prostate cancer. We report a case of AR-negative prostate cancer driven by a DOT1L-HES6 fusion gene which directly induces overexpression and patho-logical activation of HES6. We set out to study late stage prostate cancer by performing whole transcriptome and genome sequencing of two AR-negative prostate cancers from distinct patients. Sample #1 was obtained at prostatectomy from a 53-year-old patient with a Gleason 5 + 5 non-metastatic tumor and a prostate specific antigen (PSA) serum level of 4.8 lg/l. The tumor cells expressed high levels of ASCL1, CHGA, SYP, and HES6, four classical markers of neuroendocrine prostate cance