Kiuru Maija, Busam Klaus J
Departments of Dermatology and Pathology, University of California Davis, Sacramento, CA, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lab Invest. 2017 Feb;97(2):146-157. doi: 10.1038/labinvest.2016.142. Epub 2017 Jan 9.
Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS. Additionally, NF1 mutations characterize certain clinicopathologic melanoma subtypes, specifically desmoplastic melanoma. This review discusses the current knowledge of the NF1 gene and neurofibromin 1 in neurofibromatosis type I and in melanoma.
RAS/MAPK信号通路的激活在黑色素瘤中至关重要。黑色素瘤可根据其主要遗传驱动因素分为四种分子亚型：BRAF突变型、NRAS突变型、NF1突变型和三野生型肿瘤。NF1蛋白，即神经纤维瘤蛋白1，通过GTPase活性负向调节RAS蛋白。NF1的种系突变会导致I型神经纤维瘤病，这是一种由RAS/MAPK信号通路失调引起的常见遗传性肿瘤综合征，即RAS病。具有NF1突变的黑色素瘤通常发生在长期暴露于阳光下的皮肤或老年个体中，显示出高突变负担，并且BRAF和NRAS为野生型。此外，NF1突变是某些临床病理黑色素瘤亚型的特征，特别是促结缔组织增生性黑色素瘤。本综述讨论了NF1基因和神经纤维瘤蛋白1在I型神经纤维瘤病和黑色素瘤中的现有知识。
