1. Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma.
- Author
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Mattox AK, Douville C, Silliman N, Ptak J, Dobbyn L, Schaefer J, Popoli M, Blair C, Judge K, Pollard K, Pratilas C, Blakeley J, Rodriguez F, Papadopoulos N, Belzberg A, and Bettegowda C
- Subjects
- Aneuploidy, Genes, Neurofibromatosis 1, Humans, Mutation, Nerve Sheath Neoplasms genetics, Neurofibroma genetics, Neurofibroma, Plexiform genetics, Neurofibromatosis 1 genetics, Neurofibrosarcoma genetics
- 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 neurofibromatosis type 1 (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., Competing Interests: AM, NS, JP, LD, JS, MP, CB, KJ, KP, JB, FR, AB No competing interests declared, CD is a consultant to Exact Sciences and is compensated with income and equity, CP 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, NP 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. Is a founder and holds equity in ManaTbio. Is a founder, holds equity, and serves on the board of directors of Haystack, Inc. 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, CB is a consultant for Depuy-Synthes, Galectin Therapeutics and Bionaut Labs, (© 2022, Mattox et al.)
- Published
- 2022
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