背景: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反应可能与调节雄激素产生的基因的种系改变有关。摄取,和转换(APUC)。
方法: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)。我们还询问了CarisPOADNA(592基因/全外显子组)和RNA(全转录组)NGS数据库。链接活动网络算法(ALAN)用于量化所有成对基因对基因的关联。使用Kaplan-Meier估计从保险索赔数据确定真实世界总生存期(OS)。
结果:六个APUC基因(HSD3B1,HSD3B2,CYP3A43,CYP11A1,CYP11B1,CYP17A1)在一组转移性肿瘤(n=208)中表现出融合基因行为。在CarisPOA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AR的表达呈静态降低,AR-V7和AR信号传导评分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的表达相关,ESR1/2和PGR。我们使用AR或APUC-6基因的RNA表达来定义与标志途径和细胞表面靶标具有差异关联的两个肿瘤亚组。
结论:与高AR或神经内分泌前列腺癌相比,APUC-6高/低AR肿瘤代表了具有良好临床结局的患者亚组。总之,在当前的基因组测试中测量APUC-6基因的聚集表达,确定了配体(而不是AR)驱动的PC,并且需要不同的治疗策略。
背景:NCI/NIH1R37CA288972-01,NCI癌症中心支持P30CA077598,DODW81XWH-22-2-0025,R01CA249279。
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.
BACKGROUND: NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.