Ultrasensitive plasma-based monitoring of tumor burden using machine-learning-guided signal enrichment.

Journal: Nature medicine
PMID: 38877116

Abstract

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGE uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGE also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGE enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition.

Authors

  • Adam J Widman
    New York Genome Center, New York, NY, USA. widmana@mskcc.org.
  • Minita Shah
    New York Genome Center, New York, NY, USA.
  • Amanda Frydendahl
    Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Daniel Halmos
    New York Genome Center, New York, NY, USA.
  • Cole C Khamnei
    New York Genome Center, New York, NY, USA.
  • Nadia Øgaard
    Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Srinivas Rajagopalan
    New York Genome Center, New York, NY, USA.
  • Anushri Arora
    New York Genome Center, New York, NY, USA.
  • Aditya Deshpande
    New York Genome Center, New York, NY, USA.
  • William F Hooper
    New York Genome Center, New York, NY, USA.
  • Jean Quentin
    New York Genome Center, New York, NY, USA.
  • Jake Bass
    New York Genome Center, New York, NY, USA.
  • Mingxuan Zhang
    New York Genome Center, New York, NY, USA.
  • Theophile Langanay
    New York Genome Center, New York, NY, USA.
  • Laura Andersen
    Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Zoe Steinsnyder
    New York Genome Center, New York, NY, USA.
  • Will Liao
    New York Genome Center, New York, NY, USA.
  • Mads Heilskov Rasmussen
    Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Tenna Vesterman Henriksen
    Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Sarah Østrup Jensen
    Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Jesper Nors
    Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Christina Therkildsen
    Gastro Unit, Copenhagen University Hospital, Amager - Hvidovre Hospital, Hvidovre, Denmark.
  • Jesus Sotelo
    New York Genome Center, New York, NY, USA.
  • Ryan Brand
    Amazon Machine Learning Solutions Lab, Amazon Web Services, Santa Clara, CA, USA.
  • Joshua S Schiffman
    New York Genome Center, New York, NY, USA.
  • Ronak H Shah
    Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Alexandre Pellan Cheng
    New York Genome Center, New York, NY, USA.
  • Colleen Maher
    Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Lavinia Spain
    Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK.
  • Kate Krause
    Mass General Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
  • Dennie T Frederick
    Mass General Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
  • Wendie den Brok
    Department of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Caroline Lohrisch
    Department of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Tamara Shenkier
    Department of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Christine Simmons
    Department of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Diego Villa
    Department of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Andrew J Mungall
    Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
  • Richard Moore
    Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
  • Elena Zaikova
    Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Viviana Cerda
    Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Esther Kong
    Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Daniel Lai
    Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Murtaza S Malbari
    Weill Cornell Medicine, New York, NY, USA.
  • Melissa Marton
    New York Genome Center, New York, NY, USA.
  • Dina Manaa
    New York Genome Center, New York, NY, USA.
  • Lara Winterkorn
    New York Genome Center, New York, NY, USA.
  • Karen Gelmon
    Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
  • Margaret K Callahan
    Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Genevieve Boland
    Mass General Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
  • Catherine Potenski
    New York Genome Center, New York, NY, USA.
  • Jedd D Wolchok
    Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Ashish Saxena
    School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Ave, 639798, Singapore.
  • Samra Turajlic
    Cancer Dynamics Laboratory, The Francis Crick Institute, London, United Kingdom.
  • Marcin Imielinski
    Institute for Precision Medicine.
  • Michael F Berger
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Sam Aparicio
    Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • Nasser K Altorki
    Weill Cornell Medicine, New York, NY, USA.
  • Michael A Postow
    Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Nicolas Robine
    New York Genome Center, New York, New York.
  • Claus Lindbjerg Andersen
    Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Dan A Landau
    New York Genome Center, New York, NY, USA. dlandau@nygenome.org.

Keywords

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