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Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters.
Linch, M; Goh, G; Hiley, C; Shanmugabavan, Y; McGranahan, N; Rowan, A; Wong, Y N S; King, H; Furness, A; Freeman, A; Linares, J; Akarca, A; Herrero, J; Rosenthal, R; Harder, N; Schmidt, G; Wilson, G A; Birkbak, N J; Mitter, R; Dentro, S; Cathcart, P; Arya, M; Johnston, E; Scott, R; Hung, M; Emberton, M; Attard, G; Szallasi, Z; Punwani, S; Quezada, S A; Marafioti, T; Gerlinger, M; Ahmed, H U; Swanton, C.
Afiliación
  • Linch M; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK;; Department of Medical Oncology, University College London Hospitals NHS Foundation Trust, London, UK.
  • Goh G; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK;; Bill Lyons Informatics Centre, UCL Cancer Institute, London, UK.
  • Hiley C; Division of Cancer Studies, King's College London, London, UK;; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
  • Shanmugabavan Y; Division of Surgery and Interventional Science, University College London, London, UK.
  • McGranahan N; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK;; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
  • Rowan A; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
  • Wong YNS; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK;; Cancer Immunology Unit, UCL Cancer Institute, London, UK;; Research Department of Haematology, UCL Cancer Institute, London, UK.
  • King H; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK.
  • Furness A; Cancer Immunology Unit, UCL Cancer Institute, London, UK;; Research Department of Haematology, UCL Cancer Institute, London, UK.
  • Freeman A; Department of Histopathology, University College London Hospitals NHS Foundation Trust, London, UK.
  • Linares J; Department of Histopathology, University College London Hospitals NHS Foundation Trust, London, UK.
  • Akarca A; Department of Histopathology, University College London Hospitals NHS Foundation Trust, London, UK.
  • Herrero J; Bill Lyons Informatics Centre, UCL Cancer Institute, London, UK.
  • Rosenthal R; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK;; Bill Lyons Informatics Centre, UCL Cancer Institute, London, UK.
  • Harder N; Definiens AG, Munich, Germany.
  • Schmidt G; Definiens AG, Munich, Germany.
  • Wilson GA; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK;; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
  • Birkbak NJ; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK;; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
  • Mitter R; Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
  • Dentro S; Cancer Genomics Laboratory, The Francis Crick Institute, London, UK;; Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.
  • Cathcart P; The Urology Centre, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
  • Arya M; Division of Surgery and Interventional Science, University College London, London, UK;; Department of Urology, UCLH NHS Foundation Trust, London, UK.
  • Johnston E; Centre for Medical Imaging, Universtiy College London, London, UK.
  • Scott R; Division of Surgery and Interventional Science, University College London, London, UK.
  • Hung M; Division of Surgery and Interventional Science, University College London, London, UK.
  • Emberton M; Division of Surgery and Interventional Science, University College London, London, UK;; Department of Urology, UCLH NHS Foundation Trust, London, UK.
  • Attard G; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK;; Department of Medical Oncology, Royal Marsden Hospital, London, UK.
  • Szallasi Z; Centre for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark;; Computational Health Informatics Program (CHIP), Harvard Medical School, Boston, USA;; MTA-SE-NAP Brain Metastasis Research Group, Semmelweis University, Budapest, Hungary.
  • Punwani S; Centre for Medical Imaging, Universtiy College London, London, UK.
  • Quezada SA; Cancer Immunology Unit, UCL Cancer Institute, London, UK;; Research Department of Haematology, UCL Cancer Institute, London, UK.
  • Marafioti T; Department of Histopathology, University College London Hospitals NHS Foundation Trust, London, UK.
  • Gerlinger M; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK;; Department of Medical Oncology, Royal Marsden Hospital, London, UK.
  • Ahmed HU; Division of Surgery and Interventional Science, University College London, London, UK;; Division of Surgery, Department of Surgery and Cancer, Imperial College London, UK;; Department of Urology, Imperial College Healthcare NHS Trust, London, UK. Electronic address: hashim.ahmed@imperial.ac.uk.
  • Swanton C; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, UK;; Department of Medical Oncology, University College London Hospitals NHS Foundation Trust, London, UK;; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK;. Electronic address: charles.
Ann Oncol ; 28(10): 2472-2480, 2017 Oct 01.
Article en En | MEDLINE | ID: mdl-28961847
ABSTRACT

BACKGROUND:

Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. PATIENTS AND

METHODS:

Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification.

RESULTS:

We demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of ß-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of ß-catenin. Analysis of all patients with activating Wnt/ß-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion.

CONCLUSIONS:

The PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/ß-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. CLINICAL TRIALS.GOV IDENTIFIER NCT02022371.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias de la Próstata Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans / Male Idioma: En Revista: Ann Oncol Asunto de la revista: NEOPLASIAS Año: 2017 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias de la Próstata Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans / Male Idioma: En Revista: Ann Oncol Asunto de la revista: NEOPLASIAS Año: 2017 Tipo del documento: Article País de afiliación: Reino Unido