前列腺癌 (PC) 是由雄激素受体 (AR) 或其配体的异常信号传导引起的，雄激素剥夺疗法 (ADT) 是治疗的基石。 ADT 反应性可能与调节雄激素产生、摄取和转化 (APUC) 的基因的种系改变有关。我们分析了来自前列腺组织 (SU2C/PCF、TCGA、获取x）。我们还询问了 Caris POA DNA（592 个基因/全外显子组）和 RNA（全转录组）NGS 数据库。连接活动网络算法 (ALAN) 用于量化所有成对的基因与基因关联。使用 Kaplan-Meier 估计值根据保险索赔数据确定真实世界的总生存期 (OS)。六个 APUC 基因（HSD3B1、HSD3B2、CYP3A43、CYP11A1、CYP11B1、CYP17A1）在一组转移性肿瘤中表现出合并基因行为（n = 208） ）。在 Caris POA 数据集中，6 个 APUC 基因 (APUC-6) 在原发性前列腺 (n = 4,490) 和转移性 (n = 2,593) 活检中表现出稳健的聚类。令人惊讶的是，APUC-6 表达升高的肿瘤具有静态较低的 AR、AR-V7 和 AR 信号评分表达，表明配体驱动的疾病生物学。 APUC-6 基因与替代类固醇激素受体、ESR1/2 和 PGR 的表达相关。我们使用 AR 或 APUC-6 基因的 RNA 表达来定义与标志通路和细胞表面靶标具有差异相关性的两个肿瘤亚组。APUC-6 高/AR-低肿瘤代表了具有良好临床结果的患者亚组，与AR 高或神经内分泌前列腺癌。总而言之，在当前基因组测试中测量 APUC-6 基因的聚合表达可识别配体（而不是 AR）驱动的 PC，并需要不同的治疗策略。NCI/NIH 1R37CA288972-01，NCI 癌症中心支持 P30 CA077598，DOD W81XWH -22-2-0025，R01 CA249279。

Prostate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADT) are a cornerstone of treatment. ADT responsiveness may be associated with germline alterations in genes that regulate androgen production, uptake, and conversion (APUC).We analyzed whole-exome sequencing (WES) and whole transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris POA DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates.Six APUC genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) exhibited coalescent gene behavior in a cohort of metastatic tumors (n = 208). In the Caris POA dataset, the 6 APUC genes (APUC-6) exhibited robust clustering in primary prostate (n = 4,490) and metastatic (n = 2,593) biopsies. Surprisingly, tumors with elevated APUC-6 expression had statically lower expression of AR, AR-V7, and AR signaling scores suggesting ligand-driven disease biology. APUC-6 genes instead associated with the expression of alternative steroid hormone receptors, ESR1/2 and PGR. We used RNA expression of AR or APUC-6 genes to define two subgroups of tumors with differential association with hallmark pathways and cell surface targets.The APUC-6 high/AR-low tumors represented a subgroup of patients with good clinical outcomes in contrast to the AR-high or neuroendocrine prostate cancers. Altogether, measuring the aggregate expression of APUC-6 genes in current genomic tests identifies PCs that are ligand- (rather than AR-) driven and require distinct therapeutic strategies.NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.