A study published in Nature (2012) characterized the mutational landscape of lethal castrate-resistant prostate cancer (CRPC). Researchers sequenced the exomes of 50 lethal, heavily-treated metastatic CRPCs and 11 treatment-naive, high-grade localized prostate cancers. They identified low mutation rates in CRPC (2.00/Mb) and confirmed its monoclonal origin. Integrating exome copy number analysis revealed disruptions in CHD1, defining a subtype of ETS fusion-negative prostate cancer. ETS2, often deleted in CRPCs, was also deregulated through mutation. Recurrent mutations in chromatin/histone modifying genes, including MLL2, were identified, with the MLL complex interacting with the androgen receptor (AR), essential for AR signaling. Novel recurrent mutations in AR collaborating factor FOXA1 were found, which repressed androgen signaling and increased tumor growth. Proteins interacting with AR, such as ERG, FOXA1, MLL2, UTX, and ASXL1, were mutated in CRPC. The study identified nine significantly mutated genes, including TP53, AR, ZFHX3, RB1, PTEN, and APC. Mutations in MLL2, OR5L1, and CDK12 were also found. The study highlighted the role of AR signaling in CRPC, with mutations in ETS2 and FOXA1 affecting tumor growth. The integration of genomic data identified a novel prostate cancer subtype, CHD1-negative/ETS-negative. The study also showed that AR signaling is maintained in CRPC through varied mechanisms. The findings provide insights into resistance mechanisms in refractory tumors and highlight the importance of AR signaling and interacting proteins in CRPC. The study's integrated genomics dataset offers a resource for studying lethal prostate cancer and resistance mechanisms to radiation and chemotherapy.A study published in Nature (2012) characterized the mutational landscape of lethal castrate-resistant prostate cancer (CRPC). Researchers sequenced the exomes of 50 lethal, heavily-treated metastatic CRPCs and 11 treatment-naive, high-grade localized prostate cancers. They identified low mutation rates in CRPC (2.00/Mb) and confirmed its monoclonal origin. Integrating exome copy number analysis revealed disruptions in CHD1, defining a subtype of ETS fusion-negative prostate cancer. ETS2, often deleted in CRPCs, was also deregulated through mutation. Recurrent mutations in chromatin/histone modifying genes, including MLL2, were identified, with the MLL complex interacting with the androgen receptor (AR), essential for AR signaling. Novel recurrent mutations in AR collaborating factor FOXA1 were found, which repressed androgen signaling and increased tumor growth. Proteins interacting with AR, such as ERG, FOXA1, MLL2, UTX, and ASXL1, were mutated in CRPC. The study identified nine significantly mutated genes, including TP53, AR, ZFHX3, RB1, PTEN, and APC. Mutations in MLL2, OR5L1, and CDK12 were also found. The study highlighted the role of AR signaling in CRPC, with mutations in ETS2 and FOXA1 affecting tumor growth. The integration of genomic data identified a novel prostate cancer subtype, CHD1-negative/ETS-negative. The study also showed that AR signaling is maintained in CRPC through varied mechanisms. The findings provide insights into resistance mechanisms in refractory tumors and highlight the importance of AR signaling and interacting proteins in CRPC. The study's integrated genomics dataset offers a resource for studying lethal prostate cancer and resistance mechanisms to radiation and chemotherapy.