Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH.
Caris Life Sciences, Phoenix, AZ.
JCO Precis Oncol. 2024 Oct;8:e2400444. doi: 10.1200/PO-24-00444. Epub 2024 Oct 2.
The acid phosphatase 1 () gene encodes low-molecular-weight protein tyrosine phosphatase, which is overexpressed in prostate cancer (PC) and a potential therapeutic target. We analyzed expression in primary/metastatic PC and its association with molecular profiles and clinical outcomes.
NextGen sequencing of DNA (592-gene/whole-exome sequencing)/RNA(whole-transcriptome sequencing) was performed for 5,028 specimens. -High/-Low expression was defined as quartile (Q4/1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for -quartile-stratified samples. Gene set enrichment analysis was used for Hallmark collection of pathways. PD-L1+(≥2+, ≥5%; SP142) was tested by immunohistochemistry. Tumor microenvironment's (TME) immune cell fractions were estimated by RNA deconvolution/quanTIseq. Overall survival (OS) was assessed from initial diagnosis/treatment initiation to death/last follow-up.
We included 3,058 (60.8%) samples from the prostate, 634 (12.6%) from lymph node metastases (LNMs), and 1,307 (26.0%) from distant metastases (DMs). expression was higher in LNM/DM than prostate (49.8/47.9 44.1 TPM; < .0001). mutations were enriched in -Q4 (37.9%[Q4] 27.0%[Q1]; < .001) among prostate samples. Pathways associated with cell cycle regulation and oxidative phosphorylation were enriched in -Q4, whereas epithelial-mesenchymal transition and tumor necrosis factor-alpha signaling via nuclear factor kappa-light-chain-enhancer of activated B-cell pathways were enriched in -Q1. Neuroendocrine and androgen receptor signaling was increased in -Q4. M2 macrophages and natural killer cell fractions were increased, whereas T cells and M1 macrophages were decreased in -Q4. While OS differences between -Q1/Q4 were not statistically significant, there was a trend for worse OS among -Q4 prostate samples (Q4 Q1: hazard ratio [HR], 1.19 [95% CI, 0.99 to 1.42]; = .06) and DM (HR, 1.12 [95% CI, 0.93 to 1.36]; = .22) but not LNM (HR, 0.98 [95% CI, 0.74 to 1.29]; = .87).
ACP1-High tumors exhibit a distinct molecular profile and cold TME, highlighting 's potential role in PC pathogenesis and novel therapeutic targeting.
酸性磷酸酶 1（）基因编码低分子量蛋白酪氨酸磷酸酶，在前列腺癌（PC）中过度表达，是潜在的治疗靶点。我们分析了原发/转移性 PC 中的表达情况及其与分子谱和临床结局的关系。
对 5028 例标本进行了下一代测序（592 基因/全外显子测序/全转录组测序）。根据每百万转录物（TPM）的四分位数（Q4/1）定义-高/低表达。对 Q4 分层样本进行 DNA 突变分析。使用 Hallmark 通路集进行基因集富集分析。通过免疫组化检测 PD-L1+（≥2+，≥5%；SP142）。通过 RNA 去卷积/quanTIseq 估计肿瘤微环境（TME）免疫细胞分数。从初始诊断/治疗开始到死亡/最后一次随访评估总生存期（OS）。
我们纳入了 3058 例（60.8%）前列腺癌、634 例（12.6%）淋巴结转移（LNM）和 1307 例（26.0%）远处转移（DM）的样本。LNM/DM 中的表达高于前列腺（49.8/47.9 44.1 TPM； <.0001）。在前列腺样本中，-Q4 中富集了 突变（37.9%[Q4] 27.0%[Q1]； <.001）。与细胞周期调控和氧化磷酸化相关的通路在 -Q4 中富集，而上皮-间充质转化和肿瘤坏死因子-α信号通过核因子 kappa-轻链增强子的 B 细胞通路在 -Q1 中富集。神经内分泌和雄激素受体信号在 -Q4 中增加。M2 巨噬细胞和自然杀伤细胞分数增加，而 T 细胞和 M1 巨噬细胞减少。虽然 -Q1/Q4 之间的 OS 差异没有统计学意义，但 -Q4 前列腺样本的 OS 趋势较差（Q4 Q1：风险比[HR]，1.19 [95%CI，0.99 至 1.42]； =.06）和 DM（HR，1.12 [95%CI，0.93 至 1.36]； =.22）但不是 LNM（HR，0.98 [95%CI，0.74 至 1.29]； =.87）。
ACP1-High 肿瘤表现出独特的分子谱和冷 TME，突出了在 PC 发病机制和新型治疗靶点中的潜在作用。
