Neurofibromatosis-1 Gene Mutational Profiles Differ Between Syndromic Disease and Sporadic Cancers.

Objectives: Variants in the neurofibromatosis type 1 (NF1) gene are not only responsible for the NF1 cancer predisposition syndrome, but also frequently identified in cancers arising in the general population. While germline variants are pathogenic, it is not known whether those that arise in cancer (somatic variants) are passenger or driver variants. To address this question, we sought to define the landscape of variants in sporadic cancers.

Methods: variants in sporadic cancers were compiled using data curated on the c-Bio database and compared with published germline variants and Genome Aggregation Database data. Pathogenicity was determined using Polyphen and Sorting Intolerant From Tolerant prediction tools.

Results: The spectrum of variants in sporadic tumors differ from those most commonly seen in individuals with NF1. In addition, the type and location of the variants in sporadic cancer differ from germline variants, where a high proportion of missense variants were found. Finally, many of the sporadic cancer variants were not predicted to be pathogenic.

Discussion: Taken together, these findings suggest that a significant proportion of variants in sporadic cancer may be passenger variants or hypomorphic alleles. Further mechanistic studies are warranted to define their unique roles in nonsyndromic cancer pathobiology.