Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders
Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders
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DOI：
10.1182/asheducation-2015.1.559
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发表时间：
2015-12-01
影响因子：
3
通讯作者：
Parsons, D. Williams
中科院分区：
文献类型：
--
作者：
Allen, Carl E.;Parsons, D. Williams
朗格汉斯细胞组织细胞增生症(LCH)、幼年性黄色肉芽肿(JXG)和埃尔德海姆-切斯特病(ECD)是具有广泛临床表现的组织细胞疾病。直到最近，发病机制一直是推测的，争论的焦点是将这些情况归类为反应性和肿瘤性。基因组学研究一直受到稀缺的组织标本的挑战，以及病变的异质性，病理组织细胞的不同渗透。全外显子组测序最近发现，与其他肿瘤性疾病相比，LCH、JXG和ECD的体细胞突变频率非常低。然而，至少在LCH和ECD的病例中，在ECD的LCH和NRAS中，MAPK通路基因的激活突变的频率非常高，最显著的是BRAF-V600E以及MAP2K1。在ECD中，PI3K途径基因PIK3CA的反复突变也已被描述。因此，这些疾病的不同临床表现可能是在髓系分化的不同阶段MAPK突变(以及来自其他途径的修饰信号)激活的累积结果。这一模式的意义包括将LCH、JXG和ECD重新定义为一组具有共同发病机制的临床多样化的髓系肿瘤疾病。该模型支持将这些疾病的治疗策略重新聚焦于基于特定突变和起源细胞(S)的个性化方法。
Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Erdheim-Chester disease (ECD) represent histiocytic disorders with a wide range of clinical manifestations. Until recently, mechanisms of pathogenesis have been speculative and debate has focused on classification of these conditions as reactive versus neoplastic. Genomic studies have been challenged by scarce tissue specimens, as well as heterogeneous nature of the lesions with variable infiltration of pathologic histiocytes. Whole-exome sequencing recently revealed a very low frequency of somatic mutations in LCH, JXG, and ECD compared to other neoplastic disorders. However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD. In ECD, recurrent mutations in the PI3K pathway gene PIK3CA have also been described. The heterogeneous clinical manifestations of these disorders may therefore be the cumulative result of activation of MAPK mutations (along with modifying signals from other pathways) at distinct stages of myeloid differentiation. Implications of this model include redefinition of LCH, JXG, and ECD as a group of clinically diverse myeloid neoplastic disorders with a common mechanism of pathogenesis. This model supports refocusing therapeutic strategies for these diseases on a personalized approach based on specific mutations and the cell(s) of origin.