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

Austin K Mattox,Fausto Rodriguez,Joy Schaefer,Nickolas Papadopoulos,Cherie Blair,Janine Ptak,Chetan Bettegowda,Lisa Dobbyn,Christopher Douville,Allan Belzberg,Christine Pratilas,Natalie Silliman,Maria Popoli,Kai Pollard,Kathy Judge,Jaishri Blakeley

doi:10.7554/elife.74238

Austin K Mattox, Fausto Rodriguez + Show 14 more

Open Access

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

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Journal: eLife	Publication Date: Mar 4, 2022
Citations: 4	License type: CC BY 4.0

Affiliation: Johns Hopkins University, Johns Hopkins Medicine

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.

Highlights

Neurofibromatosis type 1 (NF1) is caused by inherited or de novo mutations in the NF1 gene that codes for the cytoplasmic protein neurofibromin[1]
In individuals diagnosed with NF1 and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year[3]
One of the most important aspects of clinical care for NF1 patients is monitoring plexiform neurofibromas (PN) for signs of malignant transformation to Malignant peripheral nerve sheath tumors (MPNST) that occurs in 10-15% of patients

Summary

Introduction

Neurofibromatosis type 1 (NF1) is caused by inherited or de novo mutations in the NF1 gene that codes for the cytoplasmic protein neurofibromin[1]. Neurofibromin is a GTPaseactivating protein (GAP) for the RAS family of proto-oncogenes, and mutations in NF1 lead to persistent RAS signaling and uncontrolled cellular growth through downstream RAF, MEK, and ERK signalling[1,2]. In individuals diagnosed with NF1 and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year[3]. 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[4]. 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

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