Genomic features of NF1-associated peripheral nerve sheath tumors: a cohort analysis from the Johns Hopkins NF1 biospecimen repository

Background Neurofibromatosis type 1 (NF1) is a prevalent inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform neurofibromas (PNF), atypical neurofibromatous neoplasms with unknown biological potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNST). Historically, therapeutic progress for PNF and MPNST has been limited in part due to restricted availability of primary tissues from patients with NF1. The successful advancement of therapeutic development for NF1-associated PNST necessitates ongoing efforts in the systematic acquisition and analysis of human tumor specimens and their corresponding model systems. Methods Patients with clinically or genetically confirmed NF1 having a clinically indicated surgical resection or biopsy of any NF1-associated tumor were invited to participate in an institutional review board (IRB) approved study for the collection and sharing of tissues and specimens. Tumors were assessed by the study pathologist, and banked in the laboratory as flash frozen tissues, paraffin embedded blocks or slides, DNA and RNA, or single cell suspensions. Efforts were made to create cell lines and patient derived xenografts (PDX) from primary human tissues. Clinical data for participating patients were fully annotated in a database that corresponds to banked tissue specimens. Applications for access to biospecimens, genomic data, and disease models, as well as de-identified clinical and molecular data are reviewed and approved with IRB oversight, to allow internal and external sharing to promote research collaboration. Results Since the inception of the JH NF1 biospecimen repository in 2016, 357 unique samples have been banked (from 183 unique patients) and include PNF (n=89), ANNUBP (n=6), MPNST (n=62), CNF (n=103), and diffuse neurofibroma (diffuse NF, n=44). Xenografts have successfully been generated from seven MPNST samples and cell lines have been generated from three PNF and seven MPNST. RNA sequencing (RNAseq) and whole genome sequencing (WES) data were generated from 73 and 114 primary human tumor samples, respectively. These pre-processed data, standardized for immediate computational analysis, are accessible through the NF Data Portal, allowing immediate interrogation. Our analysis herein highlights key genetic variants and alterations in gene expression patterns, linked to pathways implicated in the pathology of the NF1-associated tumor types represented in the dataset. This work also combines new sample data with previously released samples, offering a comprehensive view of the entire cohort sequenced to date. Somatic variants in genes including NF1 , SUZ12 and LRP1 and LRP2 were identified in MPNST. Enrichment of RAS-RTK signaling pathways was identified through analysis of variants in both PNF and MPNST, however, MPNST demonstrated unique enrichment in pathways associated with extracellular matrix organization and cell cycle regulation. Conclusion Analysis of primary human tissue samples is critical for identification of therapeutically relevant molecular alterations. As a dedicated effort to systematically bank tumor samples from people with NF1 undergoing surgery, in collaboration with molecular geneticists and computational biologists who seek to advance understanding of NF1 biology, the Johns Hopkins NF1 biospecimen repository offers access to samples and genomic data to the NF1 research community to promote advancement of NF1-related therapies. ### Competing Interest Statement The authors have declared no competing interest.