Garcia de Herreros Marta, Jiménez Natalia, Padrosa Joan, Aversa Caterina, Ferrer-Mileo Laura, García-Esteve Samuel, Rodríguez-Carunchio Leonardo, Trias Isabel, Fernández-Mañas Laia, Marín-Aguilera Mercedes, Altamirano Mariana, Mazariegos Manuel, Font Albert, Rodriguez-Vida Alejo, Climent Miguel Ángel, Cros Sara, Chirivella Isabel, Figols Mariona, Sala-González Núria, Ruiz de Porras Vicenç, Pardo Juan Carlos, Prat Aleix, Reig Òscar, Mellado Begoña
Translational Genomics and Targeted Therapeutics in Solid Tumors Lab, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 08036 Barcelona, Spain.
Medical Oncology Department, Hospital Clínic, 08036 Barcelona, Spain.
Int J Mol Sci. 2025 Jun 28;26(13):6244. doi: 10.3390/ijms26136244.
Alterations in the tumor suppressor gene are common in prostate cancer. They have been associated with a more aggressive disease and poor outcomes and potential benefit of targeted therapies. The purpose of this work is to study the clinical and transcriptional landscapes associated to low mRNA expression in metastatic hormone-sensitive prostate cancer (mHSPC) patients. A multicenter biomarker ambispective study was performed in mHSPC patients. mRNA expression was assessed by nCounter in formalin-fixed paraffin-embedded tumor samples. PTEN status was defined by a previously validated cut-off and was correlated with castration-resistant prostate cancer (CRPC)-free survival (CRPC-FS) (primary endpoint) and overall survival (OS). RNA-Seq was performed to molecularly characterize PTEN vs. PTEN tumors. A total of 380 patients were included, 350 eligible. PTEN was observed in 28.2% of patients and was independently associated with shorter CRPC-FS (HR 1.6, 95% CI 1.2-2.1, = 0.002) and OS (HR 1.5, 95% CI 1.1-2, = 0.014). PTEN tumors showed overexpression of neuroendocrine, cell cycle, and DNA repair gene signatures, reduced expression of the androgen receptor pathway, and a distinct immune microenvironment. Using microarray data from the CHAARTED trial, we developed a PTEN-low related signature, independently associated with CRPC-FS (HR 1.5, 95% CI 1-2.3, = 0.036) and OS (HR 1.9, C1 1.2-2.9, = 0.005), and identified targets for potential therapies in PTEN-altered tumors. We conclude that PTEN correlates with an aggressive clinical outcome in mHSPC patients and is associated with a unique transcriptional profile. These findings further support the investigation of novel therapeutic strategies for patients with alterations.
肿瘤抑制基因的改变在前列腺癌中很常见。它们与更具侵袭性的疾病、不良预后以及靶向治疗的潜在益处相关。这项工作的目的是研究转移性激素敏感性前列腺癌（mHSPC）患者中与低mRNA表达相关的临床和转录情况。对mHSPC患者进行了一项多中心生物标志物双盲研究。通过nCounter在福尔马林固定石蜡包埋的肿瘤样本中评估mRNA表达。PTEN状态通过先前验证的临界值定义，并与去势抵抗性前列腺癌（CRPC）无进展生存期（CRPC-FS，主要终点）和总生存期（OS）相关。进行RNA测序以对PTEN与PTEN肿瘤进行分子特征分析。共纳入380例患者，其中350例符合条件。28.2%的患者观察到PTEN，其与较短的CRPC-FS（HR 1.6，95%CI 1.2 - 2.1，P = 0.002）和OS（HR 1.5，95%CI 1.1 - 2，P = 0.014）独立相关。PTEN肿瘤显示神经内分泌、细胞周期和DNA修复基因特征的过表达，雄激素受体途径的表达降低，以及独特的免疫微环境。利用CHAARTED试验的微阵列数据，我们开发了一种与PTEN低表达相关的特征，其与CRPC-FS（HR 1.5，95%CI 1 - 2.3，P = 0.036）和OS（HR 1.9，C1 1.2 - 2.9，P = 0.005）独立相关，并确定了PTEN改变肿瘤中潜在治疗的靶点。我们得出结论，PTEN与mHSPC患者的侵袭性临床结果相关，并与独特的转录谱相关。这些发现进一步支持了对PTEN改变患者新型治疗策略的研究。
