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.

Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1

“…Neurofibromatosis type 1 is a rare disease and a member of the family of RASopathies (diseases caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway) that occurs in approximately 1 in 3000 patients worldwide and gives rise to cognitive impairment, skeletal abnormalities, and various nerve tumors including gliomas and neurofibromas and is caused by a mutation or deletion in one NF1 allele [1][2][3]. Nerve sheath tumors affect more than 90% of NF1 patients, mostly in the form of cutaneous neurofibromas (cNFs).…”

“…Previous genomic profiling studies have demonstrated that many NF1 nerve sheath tumors (MPNST being the exception) are genetically quiet [3,[15][16][17] and lack specific signatures that are predictive of drug response. An approach to compensate for the lack of genetic hotspots in NF1 tumors is to focus on combinations of transcriptomic signatures that may be unique to specific tumor types.…”

“…However, comprehensive analysis of genomic data in NF1 tumors is limited [3]. To enable a larger landscape analysis of NF1 nerve sheath tumors, samples from different studies were collated into a single resource as part of the NF Open Science Initiative, a collaboration between NF-related funding agencies.…”

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

“…Neurofibromatosis type 1 is a neuropathic syndrome that occurs in approximately 1 in 3000 patients worldwide and gives rise to cognitive impairment, skeletal abnormalities and various nerve tumors including gliomas and neurofibromas and is caused by a mutation or deletion in one NF1 allele [1][2][3]. Nerve sheath tumors affect more than 90% of NF1 patients, mostly in the form of cutaneous neurofibromas (cNFs).…”

Robust surgical approach for cutaneous neurofibroma in neurofibromatosis type 1

“…unknown, cNFs are affected by genetic variation of NF1, the skin microenvironment, and hormones and may grow in evolving stages (Figure 1; refs. 8,9). They are classified by stage according to appearance: the nascent stage detected only through ultrasound or other forms of imaging, the flat stage depicted by thinning or hyperpigmentation at the surface of the skin, the sessile stage with a raised papule, the globular stage with a 20-to 30-mm base with comparable height, and the pedunculated stage, which extrudes its dermal contents through a visible stalk connecting the portions above and below the skin (9,10).…”