Use of Noninvasive Biomarkers and Advanced MRI for early detection of NF1-associated MPNSTs

Approximately 120,000 Americans with neurofibromatosis type I (NF1) suffer a constellation of clinical manifestations, including aberrant proliferation of neural tissues leading to malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are highly aggressive sarcomas with a high risk of recurring and spreading, resulting in a 5-year survival rate of less than 25%. Early diagnosis and intervention offer the best outcomes. However, the lack of convenient and specific diagnostic tools is a major barrier to optimal therapeutic intervention. Conventional imaging modalities such as computed tomography (CT scan) and 18F-fluoro-d-glucose positron emission tomography scans (PET scan) are insufficiently specific. Further, lesion biopsies are extremely painful and have limited value due to the heterogeneity of these tumors. Therefore, accurate biomarkers for diagnosis and post-treatment monitoring of MPNSTs are critically needed. The long-term goal of this proposal is to deploy cfDNA-based biomarkers in patients with NF1 into routine clinical use to improve early detection of malignant transformation and monitor responses to therapy. The objective of this proposal is to establish a diagnostic panel of DNA methylation markers, cfDNA-derived tumor fraction, and aneuploidy profiles that correlate with and complement imaging-based modalities for a clinically effective tool to distinguish the presence of MPNSTs from plexiform neurofibromas. Our central hypothesis is that MPNSTs arising in patients with NF1 have unique DNA methylation and somatic chromosomal copy number profiles (aneuploidy) that can be detected in the plasma and serve as clinical biomarkers for early diagnosis or guide therapeutic strategies. We propose 4 Specific Aims: 1) Demonstrate methylation profiles as biomarkers of MPNST in plasma samples; 2) Establish aneuploidy and tumor fraction as biomarkers of MPNST; 3) Evaluate the role of advanced MRI in the early detection of MPNST; 4) Determine the feasibility of cfDNA biomarkers to predict malignant transformation and recurrent disease. Upon conclusion, we anticipate the development and validation of cfDNA methylation markers, cfDNA-derived tumor fraction, and aneuploidy profiles that can complement imaging-based modalities and can help physicians in the early detection of MPNST. Our studies are significant because they will facilitate early and accurate diagnosis of these aggressive tumors and, consequently, expedite appropriate treatment, thereby improving patient quality of life, including survival.