The NF1 somatic mutational landscape in sporadic human cancers.
The NF1 somatic mutational landscape in sporadic human cancers.
复制标题
DOI：
10.1186/s40246-017-0109-3
复制
发表时间：
2017-06-21
期刊：
影响因子：
4.5
通讯作者：
Upadhyaya M
中科院分区：
文献类型：
--
作者：
Philpott C;Tovell H;Frayling IM;Cooper DN;Upadhyaya M
1型神经纤维瘤病（NF 1：Online Mendelian Inheritance in Man（OMIM）#162200）是一种常染色体显性遗传的肿瘤易感综合征。NF 1基因中的遗传性结构突变导致RAS/MAPK通路的失调，并且是NF 1的病因。NF 1基因产物神经纤维蛋白的主要已知功能是下调RAS。NF 1表现出不同的临床表达，其特征在于良性皮肤病变，包括神经纤维瘤和咖啡牛奶斑，以及易患各种类型的恶性肿瘤，如乳腺癌和白血病。然而，获得性体细胞突变在NF 1中也被发现在各种各样的恶性肿瘤，不相关的NF 1。利用来自癌症基因组和外显子组的下一代测序数据的可用性，我们回顾了目前在许多不同位点发生的各种肿瘤中体细胞NF 1突变的知识：乳腺、结肠直肠、泌尿系统、肺、卵巢、皮肤、脑和神经内分泌组织以及白血病，以试图了解它们更广泛的作用和意义，并最终着眼于在诊断和治疗环境中利用这一点。由于神经纤维蛋白活性是调节RAS/MAPK通路的关键，因此NF 1突变在黑色素瘤、肺癌和乳腺癌以及神经母细胞瘤中获得对BRAF、EGFR抑制剂、他莫昔芬和视黄酸的耐药性方面很重要。观察到其他奇怪的现象，如皮肤黑色素瘤、肺癌、卵巢癌和胶质母细胞瘤中的体细胞NF 1突变率高，这些通常与1型神经纤维瘤病无关。体细胞NF 1突变可能是多种癌症的关键驱动因素。体细胞NF 1突变的突变景观应该为我们理解癌症的病理生理学提供新的见解。在散发性肿瘤中发现高频率的体细胞NF 1突变表明，神经纤维蛋白可能在发展中发挥关键作用，远远超出肿瘤易感综合征NF 1中的明显作用。
Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and café-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1. Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context. As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.