Abstract / Summary
Abstract Background Neurofibromatosis type 1 (NF-1), the most common neurogenetic cancer predisposition syndrome, is caused by germline mutation of the NF1 gene. NF-1 individuals exhibit marked clinical heterogeneity and malignant tumor risk. Methods We retrospectively identified 348 people treated at the University of California San Francisco between 2015–2026 who met diagnostic criteria for NF-1. Germline NF1 variant information was available in 149 patients (42.8%). Results NF-1 diagnostic criteria included café-au-lait macules (n = 281/81%), ≥2 neurofibromas (n = 252/72%), axillary/inguinal freckling (n = 225/65%), cutaneous neurofibromas (n = 175/50%), and plexiform neurofibromas (PN) (n = 188/54%). Nervous system tumors were common including malignant peripheral nerve sheath tumors (MPNSTs) (n = 63/18%), non-optic low-grade gliomas (n = 51/15%), optic glioma (n = 47/13%), and atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) (n = 27/8%). Multivariable Cox proportional hazards analysis revealed MPNST (HR 15.18, 95% CI 6.26-36.83, p < 0.001) and high-grade gliomas (HR 13.35, 95% CI 3.14-56.75, p < 0.001) were significantly associated with decreased OS. On multivariable analysis, plexiform neurofibroma (OR 2.43, 95% CI 1.30–4.57, p = 0.006) and ANNUBP (OR 3.34, 95% CI 1.42–7.87, p = 0.006) were significantly associated with increased MPNST risk; age and female sex were not independently associated with MPNST risk (Table 2). Germline NF1 variant class was not associated with MPNST risk. Conclusions MPNST was the predominant cause of cancer-related death within this tertiary-referral cohort, consistent with population-based series identifying MPNST as a leading cause of NF-1-associated mortality. Germline NF1 variant class was not associated with MPNST risk.