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

Research output: Contribution to journalArticlepeer-review

24 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 languageEnglish (US)
Pages (from-to)89848-89866
Number of pages19
JournalOncotarget
Volume8
Issue number52
DOIs
StatePublished - 2017

Keywords

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

ASJC Scopus subject areas

  • Oncology

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