A study published in Nature Medicine (2016) explores the divergent clonal evolution of castration-resistant neuroendocrine prostate cancer (CRPC-NE). The research reveals that CRPC-NE and castration-resistant adenocarcinoma (CRPC-Adeno) share genomic similarities but exhibit distinct epigenetic profiles. Whole exome sequencing and DNA methylation analysis show that CRPC-NE tumors have lower AR expression and distinct genetic alterations, including loss of RB1 and TP53, and reduced AR signaling. These findings suggest that CRPC-NE may arise from clonal evolution of CRPC-Adeno cells, rather than from pre-existing neuroendocrine clones. Epigenetic changes, such as hypermethylation of SPDEF, are also associated with CRPC-NE. The study also identifies a molecular classifier for CRPC-NE based on 70 genes, which shows high accuracy in distinguishing CRPC-NE from other prostate cancers. The results highlight the importance of epigenetic factors in the development and maintenance of CRPC-NE, and suggest that this subtype may represent a distinct, AR-independent state. The study underscores the need for improved diagnostic tools and therapeutic strategies for CRPC-NE, which is associated with poor prognosis and resistance to conventional therapies. The findings support the idea that CRPC-NE arises through divergent clonal evolution, with selective pressure driving the emergence of AR-independent features. The study also highlights the potential of epigenetic modifiers, such as EZH2 inhibitors, in targeting CRPC-NE. Overall, the research provides new insights into the molecular mechanisms underlying CRPC-NE and emphasizes the importance of integrating genomic, transcriptomic, and epigenomic data for better understanding and treatment of this aggressive form of prostate cancer.A study published in Nature Medicine (2016) explores the divergent clonal evolution of castration-resistant neuroendocrine prostate cancer (CRPC-NE). The research reveals that CRPC-NE and castration-resistant adenocarcinoma (CRPC-Adeno) share genomic similarities but exhibit distinct epigenetic profiles. Whole exome sequencing and DNA methylation analysis show that CRPC-NE tumors have lower AR expression and distinct genetic alterations, including loss of RB1 and TP53, and reduced AR signaling. These findings suggest that CRPC-NE may arise from clonal evolution of CRPC-Adeno cells, rather than from pre-existing neuroendocrine clones. Epigenetic changes, such as hypermethylation of SPDEF, are also associated with CRPC-NE. The study also identifies a molecular classifier for CRPC-NE based on 70 genes, which shows high accuracy in distinguishing CRPC-NE from other prostate cancers. The results highlight the importance of epigenetic factors in the development and maintenance of CRPC-NE, and suggest that this subtype may represent a distinct, AR-independent state. The study underscores the need for improved diagnostic tools and therapeutic strategies for CRPC-NE, which is associated with poor prognosis and resistance to conventional therapies. The findings support the idea that CRPC-NE arises through divergent clonal evolution, with selective pressure driving the emergence of AR-independent features. The study also highlights the potential of epigenetic modifiers, such as EZH2 inhibitors, in targeting CRPC-NE. Overall, the research provides new insights into the molecular mechanisms underlying CRPC-NE and emphasizes the importance of integrating genomic, transcriptomic, and epigenomic data for better understanding and treatment of this aggressive form of prostate cancer.