Masonic Cancer Center, and.
Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
JCI Insight. 2024 Oct 22;9(20):e183158. doi: 10.1172/jci.insight.183158.
BACKGROUNDProstate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADTs) are a cornerstone of treatment. ADT responsiveness may be associated with germline changes in genes that regulate androgen production, uptake, and conversion (APUC).METHODSWe analyzed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris Precision Oncology Alliance (POA) DNA (592-gene/whole exome) and RNA (whole transcriptome) next-generation sequencing databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival was determined from insurance claims data using Kaplan-Meier estimates.RESULTSSix 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 2 subgroups of tumors with differential association with hallmark pathways and cell surface targets.CONCLUSIONSThe APUC-6-high/AR-low tumors represented a subgroup of patients with good clinical outcomes, in contrast with the AR-high or neuroendocrine PCs. 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.FUNDINGNCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.
前列腺癌（PC）是由雄激素受体（AR）或其配体的异常信号驱动的，雄激素剥夺疗法（ADT）是治疗的基石。ADT 的反应性可能与调节雄激素产生、摄取和转化（APUC）的基因的种系变化有关。
我们分析了前列腺组织的全外显子组测序（WES）和全转录组测序（WTS）数据（SU2C/PCF、TCGA、GETx）。我们还研究了 Caris Precision Oncology Alliance（POA）DNA（592 基因/全外显子）和 RNA（全转录组）下一代测序数据库。算法用于链接活动网络（ALAN）用于量化所有基因对基因的关联。使用 Kaplan-Meier 估计从保险索赔数据中确定真实世界的总体生存率。
在转移性肿瘤队列（n = 208）中，有 6 个 APUC 基因（HSD3B1、HSD3B2、CYP3A43、CYP11A1、CYP11B1、CYP17A1）表现出凝聚的基因行为。在 Caris POA 数据集，6 个 APUC 基因（APUC-6）在原发性前列腺（n = 4490）和转移性（n = 2593）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 AR、AR-V7 和 AR 信号评分的表达却较低，表明存在配体驱动的疾病生物学。APUC-6 基因与替代甾体激素受体 ESR1/2 和 PGR 的表达相关。我们使用 AR 或 APUC-6 基因的 RNA 表达来定义与标志性途径和细胞表面靶标具有不同关联的肿瘤亚组。
APUC-6-高/AR-低肿瘤代表了一组具有良好临床结果的患者，与 AR-高或神经内分泌 PC 不同。总之，在当前的基因组测试中测量 APUC-6 基因的总表达，可识别出受配体（而非 AR）驱动的 PC，需要采用不同的治疗策略。
NCI/NIH 1R37CA288972-01、NCI 癌症中心支持 P30 CA077598、DOD W81XWH-22-2-0025、R01 CA249279。
