Cutaneous neurofibromas in the genomics era: current understanding and open questions

Abstract

Cutaneous neurofibromas (cNF) are a nearly ubiquitous symptom of neurofibromatosis type 1 (NF1), a disorder with a broad phenotypic spectrum caused by germline mutation of the neurofibromatosis type 1 tumour suppressor gene (NF1). Symptoms of NF1 can include learning disabilities, bone abnormalities and predisposition to tumours such as cNFs, plexiform neurofibromas, malignant peripheral nerve sheath tumours and optic nerve tumours. There are no therapies currently approved for cNFs aside from elective surgery, and the molecular aetiology of cNF remains relatively uncharacterised. Furthermore, whereas the biallelic inactivation of NF1 in neoplastic Schwann cells is critical for cNF formation, it is still unclear which additional genetic, transcriptional, epigenetic, microenvironmental or endocrine changes are important. Significant inroads have been made into cNF understanding, including NF1 genotype-phenotype correlations in NF1 microdeletion patients, the identification of recurring somatic mutations, studies of cNF-invading mast cells and macrophages, and clinical trials of putative therapeutic targets such as mTOR, MEK and c-KIT. Despite these advances, several gaps remain in our knowledge of the associated pathogenesis, which is further hampered by a lack of translationally relevant animal models. Some of these questions may be addressed in part by the adoption of genomic analysis techniques. Understanding the aetiology of cNF at the genomic level may assist in the development of new therapies for cNF, and may also contribute to a greater understanding of NF1/RAS signalling in cancers beyond those associated with NF1. Here, we summarise the present understanding of cNF biology, including the pathogenesis, mutational landscape, contribution of the tumour microenvironment and endocrine signalling, and the historical and current state of clinical trials for cNF. We also highlight open access data resources and potential avenues for future research that leverage recently developed genomics-based methods in cancer research.

Fig. 1

Cutaneous neurofibromas in NF1 patients. Cutaneous neurofibromas occur in nearly all NF1 patients, but they present with great diversity in both tumour frequency and tumour size.^– These tumours represent one of the most challenging burdens for neurofibromatosis type 1 patients.^,, Images are used with patient permission

Fig. 2

The RAS signalling cascade and tumour microenvironment in cNF. a Loss of NF1 reduces the ability of Ras to hydrolyse GTP and shift from an active to a GDP-bound inactive state. Consequently, Schwann cells lacking NF1 have increased proliferation and altered transcription (RAF-MEK-ERK signalling) and increased prosurvival signalling (PI3K-mTOR). b The cNF microenvironment is composed of NF1-deficient Schwann cells, mast cells, fibroblasts, macrophages and neurons, among other cell types. While roles for some of these cell types have been studied or hypothesised, particularly with regard to mast cells, the bulk of these cellular interactions are poorly understood or unstudied