Genomic hallmarks of localized, non-indolent prostate cancer

Michael Fraser; Veronica Y. Sabelnykova; Takafumi N. Yamaguchi; Lawrence E. Heisler; Julie Livingstone; Vincent Huang; Yu Jia Shiah; Fouad Yousif; Xihui Lin; Andre P. Masella; Natalie S. Fox; Michael Xie; Stephenie D. Prokopec; Alejandro Berlin; Emilie Lalonde; Musaddeque Ahmed; Dominique Trudel; Xuemei Luo; Timothy A. Beck; Alice Meng; Junyan Zhang; Alister D'Costa; Robert E. Denroche; Haiying Kong; Shadrielle Melijah G. Espiritu; Melvin L.K. Chua; Ada Wong; Taryne Chong; Michelle Sam; Jeremy Johns; Lee Timms; Nicholas B. Buchner; Michèle Orain; Valérie Picard; Helène Hovington; Alexander Murison; Ken Kron; Nicholas J. Harding; Christine P'ng; Kathleen E. Houlahan; Kenneth C. Chu; Bryan Lo; Francis Nguyen; Constance H. Li; Ren X. Sun; Richard De Borja; Christopher I. Cooper; Julia F. Hopkins; Shaylan K. Govind; Clement Fung; Daryl Waggott; Jeffrey Green; Syed Haider; Michelle A. Chan-Seng-Yue; Esther Jung; Zhiyuan Wang; Alain Bergeron; Alan Dal Pra; Louis Lacombe; Colin C. Collins; Cenk Sahinalp; Mathieu Lupien; Neil E. Fleshner; Housheng H. He; Yves Fradet; Bernard Tetu; Theodorus Van Der Kwast; John D. McPherson; Robert G. Bristow; Paul C. Boutros

doi:10.1038/nature20788

Genomic hallmarks of localized, non-indolent prostate cancer

Michael Fraser, Veronica Y. Sabelnykova, Takafumi N. Yamaguchi, Lawrence E. Heisler, Julie Livingstone, Vincent Huang, Yu Jia Shiah, Fouad Yousif, Xihui Lin, Andre P. Masella, Natalie S. Fox, Michael Xie, Stephenie D. Prokopec, Alejandro Berlin, Emilie Lalonde, Musaddeque Ahmed, Dominique Trudel, Xuemei Luo, Timothy A. Beck, Alice MengJunyan Zhang, Alister D'Costa, Robert E. Denroche, Haiying Kong, Shadrielle Melijah G. Espiritu, Melvin L.K. Chua, Ada Wong, Taryne Chong, Michelle Sam, Jeremy Johns, Lee Timms, Nicholas B. Buchner, Michèle Orain, Valérie Picard, Helène Hovington, Alexander Murison, Ken Kron, Nicholas J. Harding, Christine P'ng, Kathleen E. Houlahan, Kenneth C. Chu, Bryan Lo, Francis Nguyen, Constance H. Li, Ren X. Sun, Richard De Borja, Christopher I. Cooper, Julia F. Hopkins, Shaylan K. Govind, Clement Fung, Daryl Waggott, Jeffrey Green, Syed Haider, Michelle A. Chan-Seng-Yue, Esther Jung, Zhiyuan Wang, Alain Bergeron, Alan Dal Pra, Louis Lacombe, Colin C. Collins, Cenk Sahinalp, Mathieu Lupien, Neil E. Fleshner, Housheng H. He, Yves Fradet, Bernard Tetu, Theodorus Van Der Kwast, John D. McPherson, Robert G. Bristow^*, Paul C. Boutros

^*Corresponding author for this work

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Original language	English
Pages (from-to)	359-364
Number of pages	6
Journal	Nature
Volume	541
Issue number	7637
DOIs	https://doi.org/10.1038/nature20788
Publication status	Published - 19 Jan 2017

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Manchester Cancer Research Centre

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nature20788

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Fraser, M., Sabelnykova, V. Y., Yamaguchi, T. N., Heisler, L. E., Livingstone, J., Huang, V., Shiah, Y. J., Yousif, F., Lin, X., Masella, A. P., Fox, N. S., Xie, M., Prokopec, S. D., Berlin, A., Lalonde, E., Ahmed, M., Trudel, D., Luo, X., Beck, T. A., ... Boutros, P. C. (2017). Genomic hallmarks of localized, non-indolent prostate cancer. Nature, 541(7637), 359-364. https://doi.org/10.1038/nature20788

@article{cfcf8faa6911408ca3bc5675931a6089,

title = "Genomic hallmarks of localized, non-indolent prostate cancer",

abstract = "Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.",

author = "Michael Fraser and Sabelnykova, {Veronica Y.} and Yamaguchi, {Takafumi N.} and Heisler, {Lawrence E.} and Julie Livingstone and Vincent Huang and Shiah, {Yu Jia} and Fouad Yousif and Xihui Lin and Masella, {Andre P.} and Fox, {Natalie S.} and Michael Xie and Prokopec, {Stephenie D.} and Alejandro Berlin and Emilie Lalonde and Musaddeque Ahmed and Dominique Trudel and Xuemei Luo and Beck, {Timothy A.} and Alice Meng and Junyan Zhang and Alister D'Costa and Denroche, {Robert E.} and Haiying Kong and Espiritu, {Shadrielle Melijah G.} and Chua, {Melvin L.K.} and Ada Wong and Taryne Chong and Michelle Sam and Jeremy Johns and Lee Timms and Buchner, {Nicholas B.} and Mich{\`e}le Orain and Val{\'e}rie Picard and Hel{\`e}ne Hovington and Alexander Murison and Ken Kron and Harding, {Nicholas J.} and Christine P'ng and Houlahan, {Kathleen E.} and Chu, {Kenneth C.} and Bryan Lo and Francis Nguyen and Li, {Constance H.} and Sun, {Ren X.} and {De Borja}, Richard and Cooper, {Christopher I.} and Hopkins, {Julia F.} and Govind, {Shaylan K.} and Clement Fung and Daryl Waggott and Jeffrey Green and Syed Haider and Chan-Seng-Yue, {Michelle A.} and Esther Jung and Zhiyuan Wang and Alain Bergeron and {Dal Pra}, Alan and Louis Lacombe and Collins, {Colin C.} and Cenk Sahinalp and Mathieu Lupien and Fleshner, {Neil E.} and He, {Housheng H.} and Yves Fradet and Bernard Tetu and {Van Der Kwast}, Theodorus and McPherson, {John D.} and Bristow, {Robert G.} and Boutros, {Paul C.}",

year = "2017",

month = jan,

day = "19",

doi = "10.1038/nature20788",

language = "English",

volume = "541",

pages = "359--364",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7637",

}

Fraser, M, Sabelnykova, VY, Yamaguchi, TN, Heisler, LE, Livingstone, J, Huang, V, Shiah, YJ, Yousif, F, Lin, X, Masella, AP, Fox, NS, Xie, M, Prokopec, SD, Berlin, A, Lalonde, E, Ahmed, M, Trudel, D, Luo, X, Beck, TA, Meng, A, Zhang, J, D'Costa, A, Denroche, RE, Kong, H, Espiritu, SMG, Chua, MLK, Wong, A, Chong, T, Sam, M, Johns, J, Timms, L, Buchner, NB, Orain, M, Picard, V, Hovington, H, Murison, A, Kron, K, Harding, NJ, P'ng, C, Houlahan, KE, Chu, KC, Lo, B, Nguyen, F, Li, CH, Sun, RX, De Borja, R, Cooper, CI, Hopkins, JF, Govind, SK, Fung, C, Waggott, D, Green, J, Haider, S, Chan-Seng-Yue, MA, Jung, E, Wang, Z, Bergeron, A, Dal Pra, A, Lacombe, L, Collins, CC, Sahinalp, C, Lupien, M, Fleshner, NE, He, HH, Fradet, Y, Tetu, B, Van Der Kwast, T, McPherson, JD, Bristow, RG & Boutros, PC 2017, 'Genomic hallmarks of localized, non-indolent prostate cancer', Nature, vol. 541, no. 7637, pp. 359-364. https://doi.org/10.1038/nature20788

TY - JOUR

T1 - Genomic hallmarks of localized, non-indolent prostate cancer

AU - Fraser, Michael

AU - Sabelnykova, Veronica Y.

AU - Yamaguchi, Takafumi N.

AU - Heisler, Lawrence E.

AU - Livingstone, Julie

AU - Huang, Vincent

AU - Shiah, Yu Jia

AU - Yousif, Fouad

AU - Lin, Xihui

AU - Masella, Andre P.

AU - Fox, Natalie S.

AU - Xie, Michael

AU - Prokopec, Stephenie D.

AU - Berlin, Alejandro

AU - Lalonde, Emilie

AU - Ahmed, Musaddeque

AU - Trudel, Dominique

AU - Luo, Xuemei

AU - Beck, Timothy A.

AU - Meng, Alice

AU - Zhang, Junyan

AU - D'Costa, Alister

AU - Denroche, Robert E.

AU - Kong, Haiying

AU - Espiritu, Shadrielle Melijah G.

AU - Chua, Melvin L.K.

AU - Wong, Ada

AU - Chong, Taryne

AU - Sam, Michelle

AU - Johns, Jeremy

AU - Timms, Lee

AU - Buchner, Nicholas B.

AU - Orain, Michèle

AU - Picard, Valérie

AU - Hovington, Helène

AU - Murison, Alexander

AU - Kron, Ken

AU - Harding, Nicholas J.

AU - P'ng, Christine

AU - Houlahan, Kathleen E.

AU - Chu, Kenneth C.

AU - Lo, Bryan

AU - Nguyen, Francis

AU - Li, Constance H.

AU - Sun, Ren X.

AU - De Borja, Richard

AU - Cooper, Christopher I.

AU - Hopkins, Julia F.

AU - Govind, Shaylan K.

AU - Fung, Clement

AU - Waggott, Daryl

AU - Green, Jeffrey

AU - Haider, Syed

AU - Chan-Seng-Yue, Michelle A.

AU - Jung, Esther

AU - Wang, Zhiyuan

AU - Bergeron, Alain

AU - Dal Pra, Alan

AU - Lacombe, Louis

AU - Collins, Colin C.

AU - Sahinalp, Cenk

AU - Lupien, Mathieu

AU - Fleshner, Neil E.

AU - He, Housheng H.

AU - Fradet, Yves

AU - Tetu, Bernard

AU - Van Der Kwast, Theodorus

AU - McPherson, John D.

AU - Bristow, Robert G.

AU - Boutros, Paul C.

PY - 2017/1/19

Y1 - 2017/1/19

N2 - Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

AB - Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

UR - http://www.scopus.com/inward/record.url?scp=85011688924&partnerID=8YFLogxK

U2 - 10.1038/nature20788

DO - 10.1038/nature20788

M3 - Article

C2 - 28068672

AN - SCOPUS:85011688924

SN - 0028-0836

VL - 541

SP - 359

EP - 364

JO - Nature

JF - Nature

IS - 7637

ER -

Genomic hallmarks of localized, non-indolent prostate cancer

Abstract

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