Spatial genomic heterogeneity within localized, multifocal prostate cancer

Paul C. Boutros; Michael Fraser; Nicholas J. Harding; Richard de Borja; Dominique Trudel; Emilie Lalonde; Alice Meng; Pablo H. Hennings-Yeomans; Andrew McPherson; Veronica Y. Sabelnykova; Amin Zia; Natalie S. Fox; Julie Livingstone; Yu-Jia Shiah; Jianxin Wang; Timothy A. Beck; Cherry L. Have; Taryne Chong; Michelle Sam; Jeremy Johns; Lee Timms; Nicholas Buchner; Ada Wong; John D. Watson; Trent T. Simmons; Christine P'ng; Gaetano Zafarana; Francis Nguyen; Xuemei Luo; Kenneth C. Chu; Stephenie D. Prokopec; Jenna Sykes; Alan Dal Pra; Alejandro Berlin; Andrew Brown; Michelle A. Chan-Seng-Yue; Fouad Yousif; Robert E. Denroche; Lauren C. Chong; Gregory M. Chen; Esther Jung; Clement Fung; Maud H. W. Starmans; Hanbo Chen; Shaylan K. Govind; James Hawley; Alister D'Costa; Melania Pintilie; Daryl Waggott; Faraz Hach; Philippe Lambin; Lakshmi B. Muthuswamy; Colin Cooper; Rosalind Eeles; David Neal; Bernard Tetu; Cenk Sahinalp; Lincoln D. Stein; Neil Fleshner; Sohrab P. Shah; Colin C. Collins; Thomas J. Hudson; John D. McPherson; Theodorus van der Kwast; Robert G. Bristow

doi:10.1038/ng.3315

Spatial genomic heterogeneity within localized, multifocal prostate cancer

Paul C. Boutros^*, Michael Fraser, Nicholas J. Harding, Richard de Borja, Dominique Trudel, Emilie Lalonde, Alice Meng, Pablo H. Hennings-Yeomans, Andrew McPherson, Veronica Y. Sabelnykova, Amin Zia, Natalie S. Fox, Julie Livingstone, Yu-Jia Shiah, Jianxin Wang, Timothy A. Beck, Cherry L. Have, Taryne Chong, Michelle Sam, Jeremy JohnsLee Timms, Nicholas Buchner, Ada Wong, John D. Watson, Trent T. Simmons, Christine P'ng, Gaetano Zafarana, Francis Nguyen, Xuemei Luo, Kenneth C. Chu, Stephenie D. Prokopec, Jenna Sykes, Alan Dal Pra, Alejandro Berlin, Andrew Brown, Michelle A. Chan-Seng-Yue, Fouad Yousif, Robert E. Denroche, Lauren C. Chong, Gregory M. Chen, Esther Jung, Clement Fung, Maud H. W. Starmans, Hanbo Chen, Shaylan K. Govind, James Hawley, Alister D'Costa, Melania Pintilie, Daryl Waggott, Faraz Hach, Philippe Lambin, Lakshmi B. Muthuswamy, Colin Cooper, Rosalind Eeles, David Neal, Bernard Tetu, Cenk Sahinalp, Lincoln D. Stein, Neil Fleshner, Sohrab P. Shah, Colin C. Collins, Thomas J. Hudson, John D. McPherson, Theodorus van der Kwast, Robert G. Bristow

^*Corresponding author for this work

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Abstract

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

Original language	English
Pages (from-to)	736–745
Journal	Nature Genetics
Volume	47
Issue number	7
DOIs	https://doi.org/10.1038/ng.3315
Publication status	Published - Jul 2015

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Boutros, P. C., Fraser, M., Harding, N. J., de Borja, R., Trudel, D., Lalonde, E., Meng, A., Hennings-Yeomans, P. H., McPherson, A., Sabelnykova, V. Y., Zia, A., Fox, N. S., Livingstone, J., Shiah, Y.-J., Wang, J., Beck, T. A., Have, C. L., Chong, T., Sam, M., ... Bristow, R. G. (2015). Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nature Genetics, 47(7), 736–745. https://doi.org/10.1038/ng.3315

@article{33170fe2c9f94261a3ef56df3cf8daf9,

title = "Spatial genomic heterogeneity within localized, multifocal prostate cancer",

abstract = "Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.",

author = "Boutros, {Paul C.} and Michael Fraser and Harding, {Nicholas J.} and {de Borja}, Richard and Dominique Trudel and Emilie Lalonde and Alice Meng and Hennings-Yeomans, {Pablo H.} and Andrew McPherson and Sabelnykova, {Veronica Y.} and Amin Zia and Fox, {Natalie S.} and Julie Livingstone and Yu-Jia Shiah and Jianxin Wang and Beck, {Timothy A.} and Have, {Cherry L.} and Taryne Chong and Michelle Sam and Jeremy Johns and Lee Timms and Nicholas Buchner and Ada Wong and Watson, {John D.} and Simmons, {Trent T.} and Christine P'ng and Gaetano Zafarana and Francis Nguyen and Xuemei Luo and Chu, {Kenneth C.} and Prokopec, {Stephenie D.} and Jenna Sykes and {Dal Pra}, Alan and Alejandro Berlin and Andrew Brown and Chan-Seng-Yue, {Michelle A.} and Fouad Yousif and Denroche, {Robert E.} and Chong, {Lauren C.} and Chen, {Gregory M.} and Esther Jung and Clement Fung and Starmans, {Maud H. W.} and Hanbo Chen and Govind, {Shaylan K.} and James Hawley and Alister D'Costa and Melania Pintilie and Daryl Waggott and Faraz Hach and Philippe Lambin and Muthuswamy, {Lakshmi B.} and Colin Cooper and Rosalind Eeles and David Neal and Bernard Tetu and Cenk Sahinalp and Stein, {Lincoln D.} and Neil Fleshner and Shah, {Sohrab P.} and Collins, {Colin C.} and Hudson, {Thomas J.} and McPherson, {John D.} and {van der Kwast}, Theodorus and Bristow, {Robert G.}",

year = "2015",

month = jul,

doi = "10.1038/ng.3315",

language = "English",

volume = "47",

pages = "736–745",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

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Boutros, PC, Fraser, M, Harding, NJ, de Borja, R, Trudel, D, Lalonde, E, Meng, A, Hennings-Yeomans, PH, McPherson, A, Sabelnykova, VY, Zia, A, Fox, NS, Livingstone, J, Shiah, Y-J, Wang, J, Beck, TA, Have, CL, Chong, T, Sam, M, Johns, J, Timms, L, Buchner, N, Wong, A, Watson, JD, Simmons, TT, P'ng, C, Zafarana, G, Nguyen, F, Luo, X, Chu, KC, Prokopec, SD, Sykes, J, Dal Pra, A, Berlin, A, Brown, A, Chan-Seng-Yue, MA, Yousif, F, Denroche, RE, Chong, LC, Chen, GM, Jung, E, Fung, C, Starmans, MHW, Chen, H, Govind, SK, Hawley, J, D'Costa, A, Pintilie, M, Waggott, D, Hach, F, Lambin, P, Muthuswamy, LB, Cooper, C, Eeles, R, Neal, D, Tetu, B, Sahinalp, C, Stein, LD, Fleshner, N, Shah, SP, Collins, CC, Hudson, TJ, McPherson, JD, van der Kwast, T & Bristow, RG 2015, 'Spatial genomic heterogeneity within localized, multifocal prostate cancer', Nature Genetics, vol. 47, no. 7, pp. 736–745. https://doi.org/10.1038/ng.3315

TY - JOUR

T1 - Spatial genomic heterogeneity within localized, multifocal prostate cancer

AU - Boutros, Paul C.

AU - Fraser, Michael

AU - Harding, Nicholas J.

AU - de Borja, Richard

AU - Trudel, Dominique

AU - Lalonde, Emilie

AU - Meng, Alice

AU - Hennings-Yeomans, Pablo H.

AU - McPherson, Andrew

AU - Sabelnykova, Veronica Y.

AU - Zia, Amin

AU - Fox, Natalie S.

AU - Livingstone, Julie

AU - Shiah, Yu-Jia

AU - Wang, Jianxin

AU - Beck, Timothy A.

AU - Have, Cherry L.

AU - Chong, Taryne

AU - Sam, Michelle

AU - Johns, Jeremy

AU - Timms, Lee

AU - Buchner, Nicholas

AU - Wong, Ada

AU - Watson, John D.

AU - Simmons, Trent T.

AU - P'ng, Christine

AU - Zafarana, Gaetano

AU - Nguyen, Francis

AU - Luo, Xuemei

AU - Chu, Kenneth C.

AU - Prokopec, Stephenie D.

AU - Sykes, Jenna

AU - Dal Pra, Alan

AU - Berlin, Alejandro

AU - Brown, Andrew

AU - Chan-Seng-Yue, Michelle A.

AU - Yousif, Fouad

AU - Denroche, Robert E.

AU - Chong, Lauren C.

AU - Chen, Gregory M.

AU - Jung, Esther

AU - Fung, Clement

AU - Starmans, Maud H. W.

AU - Chen, Hanbo

AU - Govind, Shaylan K.

AU - Hawley, James

AU - D'Costa, Alister

AU - Pintilie, Melania

AU - Waggott, Daryl

AU - Hach, Faraz

AU - Lambin, Philippe

AU - Muthuswamy, Lakshmi B.

AU - Cooper, Colin

AU - Eeles, Rosalind

AU - Neal, David

AU - Tetu, Bernard

AU - Sahinalp, Cenk

AU - Stein, Lincoln D.

AU - Fleshner, Neil

AU - Shah, Sohrab P.

AU - Collins, Colin C.

AU - Hudson, Thomas J.

AU - McPherson, John D.

AU - van der Kwast, Theodorus

AU - Bristow, Robert G.

PY - 2015/7

Y1 - 2015/7

N2 - Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

AB - Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

U2 - 10.1038/ng.3315

DO - 10.1038/ng.3315

M3 - Article

SN - 1061-4036

VL - 47

SP - 736

EP - 745

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -