Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

SU2C/PCF West Coast Prostate Cancer Dream Team; Cameron Herberts; Matti Annala; Joonatan Sipola; Sarah W.S. Ng; Xinyi E. Chen; Anssi Nurminen; Olga V. Korhonen; Aslı D. Munzur; Kevin Beja; Elena Schönlau; Cecily Q. Bernales; Elie Ritch; Jack V.W. Bacon; Nathan A. Lack; Matti Nykter; Rahul Aggarwal; Eric J. Small; Martin E. Gleave; David A. Quigley; Felix Y. Feng; Kim N. Chi; Alexander W. Wyatt

doi:10.1038/s41586-022-04975-9

Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

SU2C/PCF West Coast Prostate Cancer Dream Team
, Cameron Herberts
, Matti Annala
, Joonatan Sipola
, Sarah W.S. Ng
, Xinyi E. Chen
, Anssi Nurminen
, Olga V. Korhonen
, Aslı D. Munzur
, Kevin Beja
, Elena Schönlau
, Cecily Q. Bernales
, Elie Ritch
, Jack V.W. Bacon
, Nathan A. Lack
, Matti Nykter
, Rahul Aggarwal
, Eric J. Small
, Martin E. Gleave
, David A. Quigley

Felix Y. Feng, Kim N. Chi, Alexander W. Wyatt^*

^*Tämän työn vastaava kirjoittaja

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

150 Sitaatiot (Scopus)

Abstrakti

Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring¹. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete^2–12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.

Alkuperäiskieli	Englanti
Sivut	199–208
Sivumäärä	10
Julkaisu	Nature
Vuosikerta	608
DOI - pysyväislinkit	https://doi.org/10.1038/s41586-022-04975-9
Tila	Julkaistu - 2022
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

This work was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence programme (project no. 312043), the Terry Fox New Frontiers Program and the BC Cancer Foundation. No funding sources were involved in the design or execution of the study. We thank S. Taavitsainen and R. Nätkin for their assistance, and are grateful to all participating patients and their families. M.A. is a shareholder in Fluivia. R.A. has received honoraria from Clovis Oncology and has served in advisory or consulting roles for Dendreon, Advanced Accelerator Applications, Clovis Oncology, Axiom Biotechnologies, AstraZeneca, Pfizer, Merck, Amgen, Jubilant Pharmaceuticals and Alessa Therapeutics. R.A. also has research funding from Zenith Epigenetics, Novartis, Xynomic Pharma, Cancer Targeted Technology, Janssen, Merck, Abbvie, Amgen, AstraZeneca and BioXCel Therapeutics. E.J.S. has stock in Fortis, Harpoon and Teon, and has received honoraria for speaking engagements for Janssen and Johnson & Johnson. E.J.S. has also served in compensated advisory or consulting roles for Janssen, Fortis, Teon and Ultragenyx. M.E.G. is the founder of OncoGenex Technologies, Sustained Therapeutics and Sitka Pharmaceuticals, and has consulted for Astellas, AstraZeneca, Bayer, Janssen, Sanofi, Pfizer, Tersera, Roche and Genova Diagnostics. D.A.Q. has consulted for Varian and Circle Pharmaceuticals. F.Y.F. has served as a consultant or advisory board member for Janssen, Celgene, Blue Earth Diagnostics, Astellas, Myovant, Roivant, Bayer, Novartis and Foundation Medicine, has stock options in Artera and has stock options and is a scientific advisory board member for SerImmune and BlueStar Genomics. K.N.C. has research funding from Janssen, Astellas and Sanofi. K.N.C. also reports research funding and personal fees from Janssen, Astellas, AstraZeneca and Sanofi, as well as personal fees from Constellation Pharmaceuticals, Daiichi Sankyo, Merck, Novartis, Pfizer, Point Biopharma and Roche outside the submitted work. A.W.W. has served on advisory boards and/or received honoraria from AstraZeneca, Astellas, Janssen, and Merck. The laboratory of A.W.W. has a contract research agreement with ESSA Pharma. C.H., J.S., S.W.S.N., X.E.C., A.N., O.V.K., A.D.M., K.B., E.S., C.Q.B., E.R., J.V.W.B., N.A.L. and M.N. declare no competing interests.

YK:n kestävän kehityksen tavoitteet

Tämä tuotos edistää seuraavia kestävän kehityksen tavoitteita:

SDG 3 – Hyvä terveys ja hyvinvointi

Julkaisufoorumi-taso

Jufo-taso 3

!!ASJC Scopus subject areas

General

Pääsy asiakirjaan

10.1038/s41586-022-04975-9

Siteeraa tätä

SU2C/PCF West Coast Prostate Cancer Dream Team, Herberts, C., Annala, M., Sipola, J., Ng, S. W. S., Chen, X. E., Nurminen, A., Korhonen, O. V., Munzur, A. D., Beja, K., Schönlau, E., Bernales, C. Q., Ritch, E., Bacon, J. V. W., Lack, N. A., Nykter, M., Aggarwal, R., Small, E. J., Gleave, M. E., ... Wyatt, A. W. (2022). Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer. Nature, 608, 199–208. https://doi.org/10.1038/s41586-022-04975-9

@article{7a967f4a42d84d89a15436007ee3a4fc,

title = "Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer",

abstract = "Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2{\textendash}12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.",

author = "\{SU2C/PCF West Coast Prostate Cancer Dream Team\} and Cameron Herberts and Matti Annala and Joonatan Sipola and Ng, \{Sarah W.S.\} and Chen, \{Xinyi E.\} and Anssi Nurminen and Korhonen, \{Olga V.\} and Munzur, \{Aslı D.\} and Kevin Beja and Elena Sch{\"o}nlau and Bernales, \{Cecily Q.\} and Elie Ritch and Bacon, \{Jack V.W.\} and Lack, \{Nathan A.\} and Matti Nykter and Rahul Aggarwal and Small, \{Eric J.\} and Gleave, \{Martin E.\} and Quigley, \{David A.\} and Feng, \{Felix Y.\} and Chi, \{Kim N.\} and Wyatt, \{Alexander W.\}",

note = "Funding Information: This work was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence programme (project no. 312043), the Terry Fox New Frontiers Program and the BC Cancer Foundation. No funding sources were involved in the design or execution of the study. We thank S. Taavitsainen and R. N{\"a}tkin for their assistance, and are grateful to all participating patients and their families. Funding Information: M.A. is a shareholder in Fluivia. R.A. has received honoraria from Clovis Oncology and has served in advisory or consulting roles for Dendreon, Advanced Accelerator Applications, Clovis Oncology, Axiom Biotechnologies, AstraZeneca, Pfizer, Merck, Amgen, Jubilant Pharmaceuticals and Alessa Therapeutics. R.A. also has research funding from Zenith Epigenetics, Novartis, Xynomic Pharma, Cancer Targeted Technology, Janssen, Merck, Abbvie, Amgen, AstraZeneca and BioXCel Therapeutics. E.J.S. has stock in Fortis, Harpoon and Teon, and has received honoraria for speaking engagements for Janssen and Johnson \& Johnson. E.J.S. has also served in compensated advisory or consulting roles for Janssen, Fortis, Teon and Ultragenyx. M.E.G. is the founder of OncoGenex Technologies, Sustained Therapeutics and Sitka Pharmaceuticals, and has consulted for Astellas, AstraZeneca, Bayer, Janssen, Sanofi, Pfizer, Tersera, Roche and Genova Diagnostics. D.A.Q. has consulted for Varian and Circle Pharmaceuticals. F.Y.F. has served as a consultant or advisory board member for Janssen, Celgene, Blue Earth Diagnostics, Astellas, Myovant, Roivant, Bayer, Novartis and Foundation Medicine, has stock options in Artera and has stock options and is a scientific advisory board member for SerImmune and BlueStar Genomics. K.N.C. has research funding from Janssen, Astellas and Sanofi. K.N.C. also reports research funding and personal fees from Janssen, Astellas, AstraZeneca and Sanofi, as well as personal fees from Constellation Pharmaceuticals, Daiichi Sankyo, Merck, Novartis, Pfizer, Point Biopharma and Roche outside the submitted work. A.W.W. has served on advisory boards and/or received honoraria from AstraZeneca, Astellas, Janssen, and Merck. The laboratory of A.W.W. has a contract research agreement with ESSA Pharma. C.H., J.S., S.W.S.N., X.E.C., A.N., O.V.K., A.D.M., K.B., E.S., C.Q.B., E.R., J.V.W.B., N.A.L. and M.N. declare no competing interests. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

doi = "10.1038/s41586-022-04975-9",

language = "English",

volume = "608",

pages = "199{\textendash}208",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

}

SU2C/PCF West Coast Prostate Cancer Dream Team, Herberts, C, Annala, M , Sipola, J, Ng, SWS, Chen, XE, Nurminen, A, Korhonen, OV, Munzur, AD, Beja, K, Schönlau, E, Bernales, CQ, Ritch, E, Bacon, JVW, Lack, NA, Nykter, M, Aggarwal, R, Small, EJ, Gleave, ME, Quigley, DA, Feng, FY, Chi, KN & Wyatt, AW 2022, 'Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer', Nature, Vuosikerta 608, Sivut 199–208. https://doi.org/10.1038/s41586-022-04975-9

TY - JOUR

T1 - Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

AU - SU2C/PCF West Coast Prostate Cancer Dream Team

AU - Herberts, Cameron

AU - Annala, Matti

AU - Sipola, Joonatan

AU - Ng, Sarah W.S.

AU - Chen, Xinyi E.

AU - Nurminen, Anssi

AU - Korhonen, Olga V.

AU - Munzur, Aslı D.

AU - Beja, Kevin

AU - Schönlau, Elena

AU - Bernales, Cecily Q.

AU - Ritch, Elie

AU - Bacon, Jack V.W.

AU - Lack, Nathan A.

AU - Nykter, Matti

AU - Aggarwal, Rahul

AU - Small, Eric J.

AU - Gleave, Martin E.

AU - Quigley, David A.

AU - Feng, Felix Y.

AU - Chi, Kim N.

AU - Wyatt, Alexander W.

N1 - Funding Information: This work was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence programme (project no. 312043), the Terry Fox New Frontiers Program and the BC Cancer Foundation. No funding sources were involved in the design or execution of the study. We thank S. Taavitsainen and R. Nätkin for their assistance, and are grateful to all participating patients and their families. Funding Information: M.A. is a shareholder in Fluivia. R.A. has received honoraria from Clovis Oncology and has served in advisory or consulting roles for Dendreon, Advanced Accelerator Applications, Clovis Oncology, Axiom Biotechnologies, AstraZeneca, Pfizer, Merck, Amgen, Jubilant Pharmaceuticals and Alessa Therapeutics. R.A. also has research funding from Zenith Epigenetics, Novartis, Xynomic Pharma, Cancer Targeted Technology, Janssen, Merck, Abbvie, Amgen, AstraZeneca and BioXCel Therapeutics. E.J.S. has stock in Fortis, Harpoon and Teon, and has received honoraria for speaking engagements for Janssen and Johnson & Johnson. E.J.S. has also served in compensated advisory or consulting roles for Janssen, Fortis, Teon and Ultragenyx. M.E.G. is the founder of OncoGenex Technologies, Sustained Therapeutics and Sitka Pharmaceuticals, and has consulted for Astellas, AstraZeneca, Bayer, Janssen, Sanofi, Pfizer, Tersera, Roche and Genova Diagnostics. D.A.Q. has consulted for Varian and Circle Pharmaceuticals. F.Y.F. has served as a consultant or advisory board member for Janssen, Celgene, Blue Earth Diagnostics, Astellas, Myovant, Roivant, Bayer, Novartis and Foundation Medicine, has stock options in Artera and has stock options and is a scientific advisory board member for SerImmune and BlueStar Genomics. K.N.C. has research funding from Janssen, Astellas and Sanofi. K.N.C. also reports research funding and personal fees from Janssen, Astellas, AstraZeneca and Sanofi, as well as personal fees from Constellation Pharmaceuticals, Daiichi Sankyo, Merck, Novartis, Pfizer, Point Biopharma and Roche outside the submitted work. A.W.W. has served on advisory boards and/or received honoraria from AstraZeneca, Astellas, Janssen, and Merck. The laboratory of A.W.W. has a contract research agreement with ESSA Pharma. C.H., J.S., S.W.S.N., X.E.C., A.N., O.V.K., A.D.M., K.B., E.S., C.Q.B., E.R., J.V.W.B., N.A.L. and M.N. declare no competing interests. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022

Y1 - 2022

N2 - Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2–12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.

AB - Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2–12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.

U2 - 10.1038/s41586-022-04975-9

DO - 10.1038/s41586-022-04975-9

M3 - Article

AN - SCOPUS:85134543022

SN - 0028-0836

VL - 608

SP - 199

EP - 208

JO - Nature

JF - Nature

ER -

Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

Abstrakti

Rahoitus

YK:n kestävän kehityksen tavoitteet

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

Pääsy asiakirjaan

Sormenjälki

Siteeraa tätä