Intratumoural evolutionary landscape of high-risk prostate cancer: The PROGENY study of genomic and immune parameters
| Autor: | Yaalini Shanmugabavan, Stefan C. Dentro, Michelle Hung, Yien Ning Sophia Wong, Paul Cathcart, Hashim U. Ahmed, Richard Mitter, J. Linares, R. Scott, Marco Gerlinger, Manit Arya, H. King, Sergio A. Quezada, N. Harder, Gerhardt Attard, Gerald Goh, Nicholas McGranahan, Edward W. Johnston, Alex Freeman, Shonit Punwani, Charles Swanton, Zoltan Szallasi, Andrew Furness, Javier Herrero, G. Schmidt, Andrew Rowan, Teresa Marafioti, Nicolai Juul Birkbak, A. Akarca, Gareth A. Wilson, Mark Linch, Rachel Rosenthal, Crispin T. Hiley, Mark Emberton |
|---|---|
| Přispěvatelé: | Wellcome Trust |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Prostate biopsy Biopsy T-Lymphocytes Gene Dosage MELANOMA medicine.disease_cause Metastasis Prostate cancer 0302 clinical medicine Urogenital Tumors Risk Factors T-Lymphocyte Subsets HETEROGENEITY Neoplasm Metastasis Wnt Signaling Pathway Wnt signalling Mutation medicine.diagnostic_test Intratumoural heterogeneity Hematology Neoepitopes prostate cancer 3. Good health mismatch repair Oncology 030220 oncology & carcinogenesis SURVIVAL Epitopes B-Lymphocyte Life Sciences & Biomedicine Somatic hypermutation Mismatch repair 03 medical and health sciences Genetic Heterogeneity tumour infiltrating lymphocytes Lymphocytes Tumor-Infiltrating SDG 3 - Good Health and Well-being Tumour infiltrating lymphocytes medicine Humans Oncology & Carcinogenesis neoepitopes Science & Technology business.industry Genetic heterogeneity intratumoural heterogeneity wnt signalling Prostatic Neoplasms Original Articles CD8 medicine.disease PD-1 BLOCKADE MSH6 Editor's Choice 030104 developmental biology MSH2 CELLS Cancer research business 1112 Oncology And Carcinogenesis |
| Zdroj: | 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 2017, ' Intratumoural evolutionary landscape of high-risk prostate cancer: The PROGENY study of genomic and immune parameters ', Annals of Oncology, vol. 28, no. 10, pp. 2472-2480 . https://doi.org/10.1093/annonc/mdx355 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 2017, ' Intratumoural evolutionary landscape of high-risk prostate cancer : The PROGENY study of genomic and immune parameters ', Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, vol. 28, no. 10, pp. 2472-2480 . https://doi.org/10.1093/annonc/mdx355 Annals of Oncology |
| Popis: | 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 β-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 β-catenin. Analysis of all patients with activating Wnt/β-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/β-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. Clinical Trials.gov Identifier NCT02022371 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|