Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

Matthew Hong; Geoff Macintyre; David Wedge; Peter Van Loo; Kavel Patel; Sebastian Lunke; Ludmil Alexandrov; Clare Sloggett; Marek Cmero; Francesco Marass; Dana Tsui; Stefano Mangiola; Andrew Lonie; Haroon Naeem; Nikhil Sapre; Pramit Phal; Natalie Kurganovs; Xiaowen Chin; Michael Kerger; Anne Y. Warren; David E. Neal; Vincent Gnanapragasam; Nitzan Rosenfeld; John Pedersen; Andrew Ryan; Izhak Haviv; Anthony J Costello; Niall Corcoran; Christopher Hovens

doi:10.1038/ncomms7605

Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

Matthew Hong, Geoff Macintyre, David Wedge, Peter Van Loo, Kavel Patel, Sebastian Lunke, Ludmil Alexandrov, Clare Sloggett, Marek Cmero, Francesco Marass, Dana Tsui, Stefano Mangiola, Andrew Lonie, Haroon Naeem, Nikhil Sapre, Pramit Phal, Natalie Kurganovs, Xiaowen Chin, Michael Kerger, Anne Y. WarrenDavid E. Neal, Vincent Gnanapragasam, Nitzan Rosenfeld, John Pedersen, Andrew Ryan, Izhak Haviv, Anthony J Costello, Niall Corcoran, Christopher Hovens

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Abstract

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

Original language	English
Article number	6605
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7605
Publication status	Published - 1 Apr 2015
Externally published	Yes

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Hong, M., Macintyre, G., Wedge, D., Van Loo, P., Patel, K., Lunke, S., Alexandrov, L., Sloggett, C., Cmero, M., Marass, F., Tsui, D., Mangiola, S., Lonie, A., Naeem, H., Sapre, N., Phal, P., Kurganovs, N., Chin, X., Kerger, M., ... Hovens, C. (2015). Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nature Communications, 6, [6605]. https://doi.org/10.1038/ncomms7605

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title = "Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer",

abstract = "Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.",

author = "Matthew Hong and Geoff Macintyre and David Wedge and {Van Loo}, Peter and Kavel Patel and Sebastian Lunke and Ludmil Alexandrov and Clare Sloggett and Marek Cmero and Francesco Marass and Dana Tsui and Stefano Mangiola and Andrew Lonie and Haroon Naeem and Nikhil Sapre and Pramit Phal and Natalie Kurganovs and Xiaowen Chin and Michael Kerger and Warren, {Anne Y.} and Neal, {David E.} and Vincent Gnanapragasam and Nitzan Rosenfeld and John Pedersen and Andrew Ryan and Izhak Haviv and Costello, {Anthony J} and Niall Corcoran and Christopher Hovens",

year = "2015",

month = apr,

day = "1",

doi = "10.1038/ncomms7605",

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Hong, M, Macintyre, G, Wedge, D, Van Loo, P, Patel, K, Lunke, S, Alexandrov, L, Sloggett, C, Cmero, M, Marass, F, Tsui, D, Mangiola, S, Lonie, A, Naeem, H, Sapre, N, Phal, P, Kurganovs, N, Chin, X, Kerger, M, Warren, AY, Neal, DE, Gnanapragasam, V, Rosenfeld, N, Pedersen, J, Ryan, A, Haviv, I, Costello, AJ, Corcoran, N & Hovens, C 2015, 'Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer', Nature Communications, vol. 6, 6605. https://doi.org/10.1038/ncomms7605

TY - JOUR

T1 - Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

AU - Hong, Matthew

AU - Macintyre, Geoff

AU - Wedge, David

AU - Van Loo, Peter

AU - Patel, Kavel

AU - Lunke, Sebastian

AU - Alexandrov, Ludmil

AU - Sloggett, Clare

AU - Cmero, Marek

AU - Marass, Francesco

AU - Tsui, Dana

AU - Mangiola, Stefano

AU - Lonie, Andrew

AU - Naeem, Haroon

AU - Sapre, Nikhil

AU - Phal, Pramit

AU - Kurganovs, Natalie

AU - Chin, Xiaowen

AU - Kerger, Michael

AU - Warren, Anne Y.

AU - Neal, David E.

AU - Gnanapragasam, Vincent

AU - Rosenfeld, Nitzan

AU - Pedersen, John

AU - Ryan, Andrew

AU - Haviv, Izhak

AU - Costello, Anthony J

AU - Corcoran, Niall

AU - Hovens, Christopher

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

AB - Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

U2 - 10.1038/ncomms7605

DO - 10.1038/ncomms7605

M3 - Article

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6605

ER -

Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

Abstract

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