Tumor and Constitutional Sequencing for Neurofibromatosis Type 1

Abstract

PURPOSE NF1 variants in tumors are important to recognize, as multiple mechanisms may give rise to biallelic variants. Both deletions and copy-neutral loss of heterozygosity (LOH) are potential mechanisms of NF1 loss, distinct from point mutations, and additional genes altered may drive different tumor types. This study investigates whether tumors from individuals with neurofibromatosis type 1 (NF1) demonstrate additional gene variants and detects NF1 second hits using paired germline and somatic sequencing. In addition, rare tumor types in NF1 may also be characterized by tumor sequencing. MATERIALS AND METHODS Sequences of 529 cancer driver genes were analyzed in 6,381 tumors, yielding 391 NF1-mutated tumors in which NF1 LOH analysis was performed. Driver genes were evaluated by tumor type including malignant peripheral nerve sheath tumors and gliomas. RESULTS NF1 LOH was seen in 133 of 391 tumor samples in the cohort. Individuals with NF1 had more prevalent copy-neutral LOH ( P < .0001), suggesting somatic intrachromosomal recombination. Osteosarcoma in NF1 also had NF1 LOH and additional p53 alteration. NF1 second hit data from tumors were informative for inferring deleteriousness of missense variants that were conflicting in ClinVar, potentially helping to add to NF1 annotation. Although criteria for evaluating germline and somatic variants are different, deleterious effects on NF1 function may be shared. CONCLUSION Sequencing of NF1-associated tumors demonstrated a spectrum of second hits in NF1 and the prevalence of copy-neutral LOH. Future work may be aimed at further understanding of LOH mechanisms and strategies to mitigate tumor risk.

Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors

“…In addition, atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) comprise an intermediate tumor entity that reflect the transition from plexiform neurofibromas to MPNSTs [ 11 ]. ANNUBPs are associated with CDKN2AB loss, and their diagnosis and classification remain an area of active investigation [ 12 •, 13 , 14 ].…”

Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma

“…Somatic ATRX mutations in PPGLs carrying germline mutations in one of the major susceptibility genes (especially in SDHB -mutated cases) have been reported ( 24 , 49 ), and this event has been described as an independent factor of poor prognosis ( 50 ). Moreover, a recent study described the co-existence of NF1 germline mutations and ATRX somatic alterations in different tumours from NF1 patients ( 51 ). Therefore, finding a PPGL carrying somatic mutations in NF1 and ATRX may not be unexpected, and warns of the malignant potential of the tumour carrying the ATRX mutation.…”

Hyperplasia of Arachnoid Trabecular Cells

“…Therefore, although the allele frequency of the NF1 variant in case 3 by WES was borderline 75% (that in case 2 was 34%) (Table S1, Supplemental Digital Content 1, http://links.lww.com/ PAS/B559), biallelic NF1 inactivation, which is virtually uniformly found in NF1-associated tumors, was not proved in cases 2 and 3. 31,32 We also examined whether they have other copy number changes suggestive of neoplastic nature by copy number analysis, and no apparent copy number changes were detected in cases 2 and 3 (Fig. S1, Supplemental Digital Content 1, http://links.…”