Intratumoural evolutionary landscape of high-risk prostate cancer: The PROGENY study of genomic and immune parameters

M. Linch, G. Goh, C. Hiley, Y. Shanmugabavan, N. McGranahan, A. Rowan, Y. N.S. Wong, H. King, A. Furness, A. Freeman, J. Linares, A. Akarca, J. Herrero, R. Rosenthal, N. Harder, G. Schmidt, G. A. Wilson, N. J. Birkbak, R. Mitter, S. DentroP. Cathcart, M. Arya, E. Johnston, R. Scott, M. Hung, M. Emberton, G. Attard, Z. Szallasi, S. Punwani, S. A. Quezada, T. Marafioti, M. Gerlinger, Hashim U. Ahmed*, Charles Swanton

*Corresponding author for this work

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    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 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.

    Original languageEnglish
    JournalAnnals of Oncology
    Volume28
    Issue number10
    Pages (from-to)2472-2480
    ISSN0923-7534
    DOIs
    Publication statusPublished - 2017

    Bibliographical note

    VC The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
    This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in
    any medium, provided the original work is properly cited.

    Keywords

    • Intratumoural heterogeneity
    • Mismatch repair
    • Neoepitopes
    • Prostate cancer
    • Tumour infiltrating lymphocytes
    • Wnt signalling

    Cite this

    Linch, M., Goh, G., Hiley, C., Shanmugabavan, Y., McGranahan, N., Rowan, A., ... Swanton, C. (2017). Intratumoural evolutionary landscape of high-risk prostate cancer: The PROGENY study of genomic and immune parameters. Annals of Oncology, 28(10), 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, Hashim U. ; Swanton, Charles. / Intratumoural evolutionary landscape of high-risk prostate cancer: The PROGENY study of genomic and immune parameters. In: Annals of Oncology. 2017 ; Vol. 28, No. 10. pp. 2472-2480.
    @article{c9e9cdc9825d45e9ae9c76778131190a,
    title = "Intratumoural evolutionary landscape of high-risk prostate cancer: The PROGENY study of genomic and immune parameters",
    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 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.",
    keywords = "Intratumoural heterogeneity, Mismatch repair, Neoepitopes, Prostate cancer, Tumour infiltrating lymphocytes, Wnt signalling",
    author = "M. Linch and G. Goh and C. Hiley and Y. Shanmugabavan and N. McGranahan and A. Rowan and Wong, {Y. N.S.} and H. King and A. Furness and A. Freeman and J. Linares and A. Akarca and J. Herrero and R. Rosenthal and N. Harder and G. Schmidt and Wilson, {G. A.} and Birkbak, {N. J.} and R. Mitter and S. Dentro and P. Cathcart and M. Arya and E. Johnston and R. Scott and M. Hung and M. Emberton and G. Attard and Z. Szallasi and S. Punwani and Quezada, {S. A.} and T. Marafioti and M. Gerlinger and Ahmed, {Hashim U.} and Charles Swanton",
    note = "VC The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.",
    year = "2017",
    doi = "10.1093/annonc/mdx355",
    language = "English",
    volume = "28",
    pages = "2472--2480",
    journal = "Annals of Oncology",
    issn = "0923-7534",
    publisher = "Oxford University Press",
    number = "10",

    }

    Linch, M, Goh, G, Hiley, C, Shanmugabavan, Y, McGranahan, N, Rowan, A, Wong, YNS, King, H, Furness, A, Freeman, A, Linares, J, Akarca, A, Herrero, J, Rosenthal, R, Harder, N, Schmidt, G, Wilson, GA, Birkbak, NJ, Mitter, R, Dentro, S, Cathcart, P, Arya, M, Johnston, E, Scott, R, Hung, M, Emberton, M, Attard, G, Szallasi, Z, Punwani, S, Quezada, SA, Marafioti, T, Gerlinger, M, Ahmed, HU & 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

    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, Hashim U.; Swanton, Charles.

    In: Annals of Oncology, Vol. 28, No. 10, 2017, p. 2472-2480.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Intratumoural evolutionary landscape of high-risk prostate cancer: The PROGENY study of genomic and immune parameters

    AU - Linch, M.

    AU - Goh, G.

    AU - Hiley, C.

    AU - Shanmugabavan, Y.

    AU - McGranahan, N.

    AU - Rowan, A.

    AU - Wong, Y. N.S.

    AU - King, H.

    AU - Furness, A.

    AU - Freeman, A.

    AU - Linares, J.

    AU - Akarca, A.

    AU - Herrero, J.

    AU - Rosenthal, R.

    AU - Harder, N.

    AU - Schmidt, G.

    AU - Wilson, G. A.

    AU - Birkbak, N. J.

    AU - Mitter, R.

    AU - Dentro, S.

    AU - Cathcart, P.

    AU - Arya, M.

    AU - Johnston, E.

    AU - Scott, R.

    AU - Hung, M.

    AU - Emberton, M.

    AU - Attard, G.

    AU - Szallasi, Z.

    AU - Punwani, S.

    AU - Quezada, S. A.

    AU - Marafioti, T.

    AU - Gerlinger, M.

    AU - Ahmed, Hashim U.

    AU - Swanton, Charles

    N1 - VC The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

    PY - 2017

    Y1 - 2017

    N2 - 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.

    AB - 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.

    KW - Intratumoural heterogeneity

    KW - Mismatch repair

    KW - Neoepitopes

    KW - Prostate cancer

    KW - Tumour infiltrating lymphocytes

    KW - Wnt signalling

    U2 - 10.1093/annonc/mdx355

    DO - 10.1093/annonc/mdx355

    M3 - Journal article

    C2 - 28961847

    AN - SCOPUS:85030564154

    VL - 28

    SP - 2472

    EP - 2480

    JO - Annals of Oncology

    JF - Annals of Oncology

    SN - 0923-7534

    IS - 10

    ER -