Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma
- Johns Hopkins University, United States
- Johns Hopkins Medicine, United States
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
Christopher Douville
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.
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.
Reviewing Editor
- Wafik S El-Deiry, Brown University, United States
Version history
- Preprint posted: September 14, 2021 (view preprint)
- Received: September 27, 2021
- Accepted: February 1, 2022
- Accepted Manuscript published: March 4, 2022 (version 1)
- 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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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
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