Clinical and Transcriptomic Characterization of Metastatic Hormone-Sensitive Prostate Cancer Patients with Low PTEN Expression

Alterations in the <i>PTEN</i> 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 <i>PTEN</i> mRNA expression in metastatic hormone-sensitive prostate cancer (mHSPC) patients. A multicenter biomarker ambispective study was performed in mHSPC patients. <i>PTEN</i> mRNA expression was assessed by nCounter in formalin-fixed paraffin-embedded tumor samples. PTEN<sub>low</sub> 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<sub>low</sub> vs. PTEN<sub>wt</sub> tumors. A total of 380 patients were included, 350 eligible. PTEN<sub>low</sub> was observed in 28.2% of patients and was independently associated with shorter CRPC-FS (HR 1.6, 95% CI 1.2-2.1, <i>p</i> = 0.002) and OS (HR 1.5, 95% CI 1.1-2, <i>p</i> = 0.014). PTEN<sub>low</sub> 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, <i>p</i> = 0.036) and OS (HR 1.9, C1 1.2-2.9, <i>p</i> = 0.005), and identified targets for potential therapies in PTEN-altered tumors. We conclude that PTEN<sub>low</sub> 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 <i>PTEN</i> alterations.

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Publication Details

Journal
International Journal of Molecular Sciences
Published
2025-06-28
DOI
https://doi.org/10.3390/ijms26136244
Citations
2
Primary Topic
Prostate Cancer Treatment and Research
Type
article
Field-Weighted Citation Impact
3.04

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article

Clinical and Transcriptomic Characterization of Metastatic Hormone-Sensitive Prostate Cancer Patients with Low PTEN Expression

Marta García de Herreros, Samuel García-Esteve, Natàlia Jiménez, Begoña Mellado et al.
2 citations
International Journal of Molecular Sciences
Prostate Cancer Treatment and Research
3.04
article

Clinical and Transcriptomic Characterization of Metastatic Hormone-Sensitive Prostate Cancer Patients with Low PTEN Expression

Marta García de Herreros, Samuel García-Esteve, Natàlia Jiménez, Begoña Mellado, Isabel Chirivella, Vicenç Ruiz de Porras, Òscar Reig, Laura Ferrer‐Mileo, Caterina Aversa, Joan Padrosa, Manuel Mazariegos, Isabel Trias, Mariona Figols, Leonardo Rodríguez‐Carunchio, Núria Sala‐González, Sara Cros, Mercedes Marín‐Aguilera, Aleix Prat, Laia Fernández-Mañas, Alejo Rodríguez‐Vida, Juan Carlos Pardo, Miguel Ángel Climent, M. Altamirano, Albert Font
article en
2 citations

Abstract

Alterations in the <i>PTEN</i> 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 <i>PTEN</i> mRNA expression in metastatic hormone-sensitive prostate cancer (mHSPC) patients. A multicenter biomarker ambispective study was performed in mHSPC patients. <i>PTEN</i> mRNA expression was assessed by nCounter in formalin-fixed paraffin-embedded tumor samples. PTEN<sub>low</sub> 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<sub>low</sub> vs. PTEN<sub>wt</sub> tumors. A total of 380 patients were included, 350 eligible. PTEN<sub>low</sub> was observed in 28.2% of patients and was independently associated with shorter CRPC-FS (HR 1.6, 95% CI 1.2-2.1, <i>p</i> = 0.002) and OS (HR 1.5, 95% CI 1.1-2, <i>p</i> = 0.014). PTEN<sub>low</sub> 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, <i>p</i> = 0.036) and OS (HR 1.9, C1 1.2-2.9, <i>p</i> = 0.005), and identified targets for potential therapies in PTEN-altered tumors. We conclude that PTEN<sub>low</sub> 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 <i>PTEN</i> alterations.

International Journal of Molecular SciencesVol. 26(13)
Universitat de València (ES), Instituto de Salud Carlos III (ES), Althaia (ES), Hospital Clínico Universitario de Valencia (ES), Fundación Instituto Valenciano de Oncología (ES), Institut Català d'Oncologia (ES), Hospital General de Granollers (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Hospital Clínic de Barcelona (ES), Hospital Del Mar (ES), Fundació Clínic per a la Recerca Biomèdica (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Instituto de Investigación de Enfermedades Raras (ES), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (ES), Universitat de Barcelona (ES)
European Commission, Janssen Pharmaceuticals
Good health and well-being
Openalex Percentile: Top 9%
Prostate Cancer Treatment and Research
3.04
DOIOpen Access PDFOpenAlex
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