Sage Bionetworks, Seattle, WA, 98109, USA.
Children's Tumor Foundation, New York, NY, 10005, USA.
Br J Cancer. 2018 Jun;118(12):1539-1548. doi: 10.1038/s41416-018-0073-2. Epub 2018 Apr 26.
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.
皮肤神经纤维瘤（cNF）是神经纤维瘤病 1 型（NF1）的一种几乎普遍存在的症状，NF1 是一种由神经纤维瘤病 1 型肿瘤抑制基因（NF1）种系突变引起的表型谱广泛的疾病。NF1 的症状包括学习障碍、骨骼异常和易患神经纤维瘤、丛状神经纤维瘤、恶性外周神经鞘瘤和视神经瘤等肿瘤。除了选择性手术外，目前尚无针对 cNF 的治疗方法，cNF 的分子病因仍相对不明确。此外，尽管肿瘤性施万细胞中 NF1 的双等位基因失活对于 cNF 的形成至关重要，但仍不清楚哪些其他遗传、转录、表观遗传、微环境或内分泌变化是重要的。在 cNF 理解方面已经取得了重大进展，包括 NF1 微缺失患者的 NF1 基因型-表型相关性、反复出现的体细胞突变的鉴定、cNF 浸润肥大细胞和巨噬细胞的研究，以及针对 mTOR、MEK 和 c-KIT 等潜在治疗靶点的临床试验。尽管取得了这些进展，但我们对相关发病机制的认识仍存在一些空白，而缺乏转化相关的动物模型进一步阻碍了这方面的研究。这些问题中的一些可能部分通过采用基因组分析技术来解决。在基因组水平上了解 cNF 的病因可能有助于开发针对 cNF 的新疗法，并且可能有助于更好地了解 NF1/RAS 信号在 NF1 相关癌症以外的癌症中的作用。在这里，我们总结了目前对 cNF 生物学的理解，包括发病机制、突变景观、肿瘤微环境和内分泌信号的贡献，以及 cNF 临床试验的历史和现状。我们还强调了开放获取的数据资源和未来研究的潜在途径，这些途径利用了癌症研究中最近开发的基于基因组的方法。
