Hannah E Bergom, Ella Boytim, Sean McSweeney, Negar Sadeghipour, Andrew Elliott, Rachel Passow, Eamon Toye, Xiuxiu Li, Pornlada Likasitwatanakul, Daniel M Geynisman, Scott M Dehm, Susan Halabi, Nima Sharifi, Emmanuel S Antonarakis, Charles J Ryan, Justin Hwang
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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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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. 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引用次数: 0
摘要
背景：前列腺癌（PC）由雄激素受体（AR）或其配体的异常信号驱动，雄激素剥夺疗法（ADT）是治疗的基础。ADT反应性可能与调节雄激素产生、摄取和转换（APUC）的基因的种系改变有关：我们分析了前列腺组织（SU2C/PCF、TCGA、GETx）的全外显子组测序（WES）和全转录组测序（WTS）数据。我们还查询了 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）用于量化所有基因对基因之间的配对关联。使用 Kaplan-Meier 估计法从保险理赔数据中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（n = 208）中表现出基因凝聚行为。在 Caris POA 数据集中，6 个 APUC 基因（APUC-6）在原发性前列腺（n = 4,490 个）和转移性前列腺（n = 2,593 个）活检中表现出强大的聚类。令人惊讶的是，APUC-6表达量升高的肿瘤，其AR、AR-V7和AR信号转导评分的表达量呈静态降低趋势，这表明配体驱动的疾病生物学特性。APUC-6基因反而与替代类固醇激素受体ESR1/2和PGR的表达有关。我们利用AR或APUC-6基因的RNA表达来定义与标志性通路和细胞表面靶点有不同关联的两个肿瘤亚组：结论：APUC-6高/AR低肿瘤代表了临床预后良好的患者亚群，与AR高或神经内分泌性前列腺癌形成鲜明对比。总之，在目前的基因组测试中测量APUC-6基因的总表达量可以确定配体（而不是AR）驱动的PC，需要不同的治疗策略：NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.
Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes.
Background: 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).
Methods: 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.
Results: 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.
Conclusions: 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.
Funding: NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.
期刊介绍：
JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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