Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are the deadliest cancer that arises in individuals diagnosed with neurofibromatosis and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year. Comprised of neoplastic Schwann cells, primary risk factors for developing MPNST include existing plexiform neurofibromas (PN), prior radiotherapy treatment, and expansive germline mutations involving the entire NF1 gene and surrounding genes. PN develop in nearly 30-50% of patients with NF1 and most often grow rapidly in the first decade of life. One of the most important aspects of clinical care for NF1 patients is monitoring PN for signs of malignant transformation to MPNST that occurs in 10-15% of patients. We perform aneuploidy analysis on ctDNA from 883 ostensibly healthy individuals and 28 patients with neurofibromas, including 7 patients with benign neurofibroma, 9 patients with PN and 12 patients with MPNST. Overall sensitivity for detecting MPNST using genome wide aneuploidy scoring was 33%, and analysis of sub-chromosomal copy number alterations (CNAs) improved sensitivity to 50% while retaining a high specificity of 97%. In addition, we performed mutation analysis on plasma cfDNA for a subset of patients and identified mutations in NF1, NF2, RB1, TP53BP2, and GOLGA2. Given the high throughput and relatively low sequencing coverage required by our assay, liquid biopsy represents a promising technology to identify incipient MPNST.

Data availability

Code is available at https://zenodo.org/record/3656943#.YaZZCdDMKUk.

Article and author information

Author details

  1. Austin K Mattox

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7567-5542
  2. Christopher Douville

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    Christopher Douville, is a consultant to Exact Sciences and is compensated with income and equity..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2510-4151
  3. Natalie Silliman

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Janine Ptak

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  5. Lisa Dobbyn

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  6. Joy Schaefer

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  7. Maria Popoli

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  8. Cherie Blair

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  9. Kathy Judge

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  10. Kai Pollard

    Department of Pediatrics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  11. Christine Pratilas

    Department of Pediatrics, Johns Hopkins University, Baltimore, United States
    Competing interests
    Christine Pratilas, is a paid consultant for Roche/ Genentech and Day One Therapeutics; and receives research funding from Kura Oncology and Novartis Institute of Biomedical Research, all for work that is outside the scope of the submitted manuscript..
  12. Jaishri Blakeley

    Department of Pediatrics, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  13. Fausto Rodriguez

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  14. Nickolas Papadopoulos

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    Competing interests
    Nickolas Papadopoulos, is a founder of Thrive Earlier Detection, an Exact Sciences Company. Is a consultant to Thrive Earlier Detection. Holds equity in Exact Sciences. Is a founder of and holds equity in Personal Genome Diagnostics. Is a consultant to Personal Genome Diagnostics. Holds equity in and is a consultant to CAGE Pharma. Owns equity in Neophore and is a consultant to Neophore. The companies named above as well as other companies have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. Is an inventor on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins University in accordance with its conflict-of-interest policies..
  15. Allan Belzberg

    Johns Hopkins Medicine, Baltimore`, United States
    For correspondence
    abelzeb1@jhmi.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1158-2117
  16. Chetan Bettegowda

    Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, United States
    For correspondence
    cbetteg1@jhmi.edu
    Competing interests
    Chetan Bettegowda, is a consultant for Depuy-Synthes, Galectin Therapeutics and Bionaut Labs..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9991-7123

Funding

National Institutes of Health (1R21CA208723-01)

  • Chetan Bettegowda

National Institutes of Health (R37 CA230400)

  • Chetan Bettegowda

National Institutes of Health (U01 CA230691)

  • Chetan Bettegowda

DOD (W81XWH-16-0078)

  • Allan Belzberg
  • Chetan Bettegowda

Doris Duke Charitable Foundation (grant 2014107)

  • Chetan Bettegowda

Burroughs Wellcome Fund (Career Award for Medical Scientists)

  • Chetan Bettegowda

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wafik S El-Deiry, Brown University, United States

Ethics

Human subjects: All individuals participating in the study provided written informed consent after approval by the institutional review board at The Johns Hopkins IRB00075499. The study complied with the Health Insurance Portability and Accountability Act and the Deceleration of Helsinki.

Version history

  1. Preprint posted: September 14, 2021 (view preprint)
  2. Received: September 27, 2021
  3. Accepted: February 1, 2022
  4. Accepted Manuscript published: March 4, 2022 (version 1)
  5. Version of Record published: May 11, 2022 (version 2)

Copyright

© 2022, Mattox et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Austin K Mattox
  2. Christopher Douville
  3. Natalie Silliman
  4. Janine Ptak
  5. Lisa Dobbyn
  6. Joy Schaefer
  7. Maria Popoli
  8. Cherie Blair
  9. Kathy Judge
  10. Kai Pollard
  11. Christine Pratilas
  12. Jaishri Blakeley
  13. Fausto Rodriguez
  14. Nickolas Papadopoulos
  15. Allan Belzberg
  16. Chetan Bettegowda
(2022)
Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma
eLife 11:e74238.
https://doi.org/10.7554/eLife.74238

Share this article

https://doi.org/10.7554/eLife.74238

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