Exploring the genetic basis for clinical variation in neurofibromatosis type 1.
Exploring the genetic basis for clinical variation in neurofibromatosis type 1.
复制标题
探索 1 型神经纤维瘤病临床变异的遗传基础。
DOI：
10.1080/14737175.2016.1189329
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发表时间：
2016
影响因子：
4.3
通讯作者：
Gutmann,DavidH
中科院分区：
文献类型：
--
作者：
Gutmann,DavidH
实施个性化患者护理方法（精准医学）的挑战之一是疾病发展和进展的预测标志物相对缺乏。在这方面，特定疾病的自然史或该疾病（例如癌症）在任何给定个体中的特定临床特征的出现由无数因素决定，从基因组（例如单核苷酸多态性）和遗传（例如特定的种系和体细胞突变）决定因素到组织（例如肿瘤微环境）和细胞（例如起源细胞）影响。同样，特定癌症对靶向治疗的反应也反映了这些因素的相互作用。为了解开这一复杂性，有必要剖析这些疾病修饰因子中的每一个的贡献。通过研究由单一基因引起的人类疾病，这一看似压倒性的任务在一定程度上得到了简化。每个患有单基因疾病的人都有一个共同的遗传病因和一系列预期的临床特征，这为旨在确定疾病异质性因素的更多对照研究提供了基础。了解这些因素造成临床变异性的机制也为建立改进的风险评估策略和为未来的临床试验确定新的治疗靶点提供了前所未有的机会。1型神经纤维瘤病（NF 1）是一种常见的单基因综合征，全世界每2500人中就有一例。患有NF 1的个体易于发展为良性（神经纤维瘤和视神经胶质瘤）和恶性（胶质母细胞瘤、乳腺癌、恶性外周神经鞘瘤和白血病）肿瘤以及心血管缺陷、自闭症、认知和运动延迟、癫痫、睡眠障碍和骨骼异常。目前，还无法预测哪个儿童或成人会出现这些医疗问题。此外，即使出现临床异常，目前也不可能准确确定该特定疾病特征的自然史。除了既往放射治疗（丛状神经纤维瘤和视神经胶质瘤）和年轻（< 2岁）或脑部位置（视交叉后神经胶质瘤）外，几乎没有疾病进展的预测因素。这些障碍促进了对终身疾病的LreactiveL（预期管理）方法，并限制了我们在决定如何最好地治疗特定临床问题时的治疗选择。在这方面，在某些情况下，治疗可能会延迟，导致毁灭性的结果，而其他人，谁可能永远不需要治疗，可能会暴露于重复的镇静射线照相程序。然而，最近的研究使用Nf 1基因工程小鼠（GEM）模型，其中一个单一的因素，可以孤立地研究，已经开始提供重要的见解的方式，这些因素中的每一个影响疾病的发病机制和进展。在NF 1患者中，流行病学和基因组研究表明，种族[1]，性别[2]和单核苷酸多态性[3]均影响NF 1儿童脑肿瘤发生和进展的风险。利用发展高级别脑肿瘤（神经胶质瘤）的Nf 1 GEM菌株，已鉴定出几个修饰基因座，这些基因座决定了神经胶质瘤的发生率和位置，而GEM低级别神经胶质瘤模型已开始阐明性别对小鼠视神经胶质瘤发生、进展和相关视力丧失的影响[4-7]。丛状神经纤维瘤和视神经胶质瘤的Nf 1 GEM模型还揭示了起源细胞和肿瘤细胞的至关重要性。
One of the challenges to implementing individualized approaches to patient care (precision medicine) is the relative paucity of predictive markers of disease development and progression. In this regard, the natural history of a particular disorder or the appearance of specific clinical features of that disease (eg cancer) in any given individual is dictated by a myriad of factors, ranging from genomic (eg singlenucleotide polymorphisms) and genetic (eg specific germline and somatic mutations) determinants to tissue (eg tumor microenvironment) and cellular (eg cell of origin) influences. Similarly, how a particular cancer responds to targeted therapies also reflects the interplay of these factors. In order to unravel this complexity, it is necessary to dissect the contributions of each of these disease modifiers. This seemingly overwhelming task is partly simplified by studying human disorders that arise from a single gene. Each person with a monogenic condition shares a common genetic etiology and a spectrum of anticipated clinical features, which provide the foundations for more controlled studies aimed at defining the factors that underlie disease heterogeneity. Understanding the mechanisms by which these contributors create clinical variability also provides unprecedented opportunities to establish improved risk assessment strategies and to identify new therapeutic targets for future clinical trials. Neurofibromatosis type 1 (NF1) is a common monogenic syndrome affecting one per 2500 individuals worldwide. Individuals with NF1 are prone to develop benign (neurofibromas and optic gliomas) and malignant (glioblastoma, breast cancer, malignant peripheral nerve sheath tumors, and leukemia) tumors as well as cardiovascular defects, autism, cognitive and motor delays, epilepsy, sleep disturbances, and skeletal abnormalities. At present, it is not possible to predict which child or adult will develop which of these medical problems. Moreover, even when clinical abnormalities arise, it is also not currently possible to accurately determine the natural history of that particular disease feature. Aside from previous radiation therapy (plexiform neurofibroma and optic glioma) and young age (< 2 years old) or brain location (postchiasmal optic glioma), few predictors of disease progression exist. These barriers foster a LreactiveL (anticipatory management) approach for a lifelong condition and limit our therapeutic options when deciding how to best treat a particular clinical problem when it arises. In this regard, treatment may be delayed in some cases, leading to devastating outcomes, while others, who might never require treatment, may be exposed to repeated sedated radiographic procedures. However, recent studies using Nf1 genetically engineered mouse (GEM) models, where a single factor can be studied in isolation, have begun to provide important insights into the manners by which each of these factors operates to influence disease pathogenesis and progression. In people with NF1, epidemiologic and genomic investigations have revealed that race [1], sex [2], and single-nucleotide polymorphisms [3] each influence the risk of brain tumor development and progression in children with NF1. Leveraging Nf1 GEM strains that develop high-grade brain tumors (gliomas), several modifier loci have been identified that dictate the penetrance and location of gliomas, while GEM low-grade glioma models have begun to elucidate the impact of sex on optic glioma development, progression, and associated vision loss in mice [4-7]. Nf1 GEM models of plexiform neurofibroma and optic glioma have additionally revealed the critical importance of the cell of origin and the tumor …