Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy

Daniel H. Hovelson; Chia Jen Liu; Yugang Wang; Qing Kang; James Henderson; Amy Gursky; Scott Brockman; Nithya Ramnath; John C. Krauss; Moshe Talpaz; Malathi Kandarpa; Rashmi Chugh; Missy Tuck; Kirk Herman; Catherine S. Grasso; Michael J. Quist; Felix Y. Feng; Christine Haakenson; John Langmore; Emmanuel Kamberov; Tim Tesmer; Hatim Husain; Robert J. Lonigro; Dan Robinson; David C. Smith; Ajjai S. Alva; Maha H. Hussain; Arul M. Chinnaiyan; Muneesh Tewari; Ryan E. Mills; Todd M. Morgan; Scott A. Tomlins

doi:10.18632/oncotarget.21163

Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy

Daniel H. Hovelson, Chia Jen Liu, Yugang Wang, Qing Kang, James Henderson, Amy Gursky, Scott Brockman, Nithya Ramnath, John C. Krauss, Moshe Talpaz, Malathi Kandarpa, Rashmi Chugh, Missy Tuck, Kirk Herman, Catherine S. Grasso, Michael J. Quist, Felix Y. Feng, Christine Haakenson, John Langmore, Emmanuel KamberovTim Tesmer, Hatim Husain, Robert J. Lonigro, Dan Robinson, David C. Smith, Ajjai S. Alva, Maha H. Hussain, Arul M. Chinnaiyan, Muneesh Tewari, Ryan E. Mills, Todd M. Morgan, Scott A. Tomlins^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

33 Scopus citations

Abstract

Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castrationresistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.

Original language	English (US)
Pages (from-to)	89848-89866
Number of pages	19
Journal	Oncotarget
Volume	8
Issue number	52
DOIs	https://doi.org/10.18632/oncotarget.21163
State	Published - 2017

Keywords

Cell-free DNA
Copy-number analysis
Precision oncology
Prostate cancer
Whole genome sequencing

ASJC Scopus subject areas

Oncology

UN SDGs

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

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10.18632/oncotarget.21163

Cite this

Hovelson, D. H., Liu, C. J., Wang, Y., Kang, Q., Henderson, J., Gursky, A., Brockman, S., Ramnath, N., Krauss, J. C., Talpaz, M., Kandarpa, M., Chugh, R., Tuck, M., Herman, K., Grasso, C. S., Quist, M. J., Feng, F. Y., Haakenson, C., Langmore, J., ... Tomlins, S. A. (2017). Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy. Oncotarget, 8(52), 89848-89866. https://doi.org/10.18632/oncotarget.21163

@article{1b453e7aa9254f79aa6f95a4974fc9c6,

title = "Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy",

abstract = "Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castrationresistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.",

keywords = "Cell-free DNA, Copy-number analysis, Precision oncology, Prostate cancer, Whole genome sequencing",

author = "Hovelson, {Daniel H.} and Liu, {Chia Jen} and Yugang Wang and Qing Kang and James Henderson and Amy Gursky and Scott Brockman and Nithya Ramnath and Krauss, {John C.} and Moshe Talpaz and Malathi Kandarpa and Rashmi Chugh and Missy Tuck and Kirk Herman and Grasso, {Catherine S.} and Quist, {Michael J.} and Feng, {Felix Y.} and Christine Haakenson and John Langmore and Emmanuel Kamberov and Tim Tesmer and Hatim Husain and Lonigro, {Robert J.} and Dan Robinson and Smith, {David C.} and Alva, {Ajjai S.} and Hussain, {Maha H.} and Chinnaiyan, {Arul M.} and Muneesh Tewari and Mills, {Ryan E.} and Morgan, {Todd M.} and Tomlins, {Scott A.}",

note = "Funding Information: We thank all patients and family members for their contributions to this work. Supported by a Michigan Corporate Relations Network (MCRN) Small Company Innovation Program (SCIP) grant to S.A.T. and E.K and the National Institutes of Health (R01 CA183857 to S.A.T., R01HG007068 to R.E.M., Transformative R01 Grant R01DK085714 to M.T., and Cancer Center Support Grant funds to M.T. via award P30CA046592 from the National Cancer Institute of the NIH). A.M.C., T.M.M. and S.A.T. are supported by the A. Alfred Taubman Medical Research Institute. A.M.C., T.M.M., and S.A.T. are supported by the Prostate Cancer Foundation. T.M.M. is supported by a Department of Defense Physician Research Training Award (W81XWH-14-1-0287). Q.K. is supported by the National Center for Advancing Translational Sciences Postdoctoral Translational Scholar Program Fellowship (UL1TR000433). Publisher Copyright: {\textcopyright} Hovelson et al.",

year = "2017",

doi = "10.18632/oncotarget.21163",

language = "English (US)",

volume = "8",

pages = "89848--89866",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "52",

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Hovelson, DH, Liu, CJ, Wang, Y, Kang, Q, Henderson, J, Gursky, A, Brockman, S, Ramnath, N, Krauss, JC, Talpaz, M, Kandarpa, M, Chugh, R, Tuck, M, Herman, K, Grasso, CS, Quist, MJ, Feng, FY, Haakenson, C, Langmore, J, Kamberov, E, Tesmer, T, Husain, H, Lonigro, RJ, Robinson, D, Smith, DC, Alva, AS, Hussain, MH, Chinnaiyan, AM, Tewari, M, Mills, RE, Morgan, TM & Tomlins, SA 2017, 'Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy', Oncotarget, vol. 8, no. 52, pp. 89848-89866. https://doi.org/10.18632/oncotarget.21163

TY - JOUR

T1 - Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy

AU - Hovelson, Daniel H.

AU - Liu, Chia Jen

AU - Wang, Yugang

AU - Kang, Qing

AU - Henderson, James

AU - Gursky, Amy

AU - Brockman, Scott

AU - Ramnath, Nithya

AU - Krauss, John C.

AU - Talpaz, Moshe

AU - Kandarpa, Malathi

AU - Chugh, Rashmi

AU - Tuck, Missy

AU - Herman, Kirk

AU - Grasso, Catherine S.

AU - Quist, Michael J.

AU - Feng, Felix Y.

AU - Haakenson, Christine

AU - Langmore, John

AU - Kamberov, Emmanuel

AU - Tesmer, Tim

AU - Husain, Hatim

AU - Lonigro, Robert J.

AU - Robinson, Dan

AU - Smith, David C.

AU - Alva, Ajjai S.

AU - Hussain, Maha H.

AU - Chinnaiyan, Arul M.

AU - Tewari, Muneesh

AU - Mills, Ryan E.

AU - Morgan, Todd M.

AU - Tomlins, Scott A.

N1 - Funding Information: We thank all patients and family members for their contributions to this work. Supported by a Michigan Corporate Relations Network (MCRN) Small Company Innovation Program (SCIP) grant to S.A.T. and E.K and the National Institutes of Health (R01 CA183857 to S.A.T., R01HG007068 to R.E.M., Transformative R01 Grant R01DK085714 to M.T., and Cancer Center Support Grant funds to M.T. via award P30CA046592 from the National Cancer Institute of the NIH). A.M.C., T.M.M. and S.A.T. are supported by the A. Alfred Taubman Medical Research Institute. A.M.C., T.M.M., and S.A.T. are supported by the Prostate Cancer Foundation. T.M.M. is supported by a Department of Defense Physician Research Training Award (W81XWH-14-1-0287). Q.K. is supported by the National Center for Advancing Translational Sciences Postdoctoral Translational Scholar Program Fellowship (UL1TR000433). Publisher Copyright: © Hovelson et al.

PY - 2017

Y1 - 2017

N2 - Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castrationresistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.

AB - Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castrationresistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.

KW - Cell-free DNA

KW - Copy-number analysis

KW - Precision oncology

KW - Prostate cancer

KW - Whole genome sequencing

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DO - 10.18632/oncotarget.21163

M3 - Article

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AN - SCOPUS:85032307371

SN - 1949-2553

VL - 8

SP - 89848

EP - 89866

JO - Oncotarget

JF - Oncotarget

IS - 52

ER -

Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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