Identification of the V600D mutation in Exon 15 of the BRAF oncogene in congenital, benign langerhans cell histiocytosis
Identification of the V600D mutation in Exon 15 of the BRAF oncogene in congenital, benign langerhans cell histiocytosis
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DOI：
10.1002/gcc.22010
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发表时间：
2013-01-01
影响因子：
3.7
通讯作者：
Nathwani, Bharat N.
中科院分区：
文献类型：
--
作者：
Kansal, Rina;Quintanilla-Martinez, Leticia;Nathwani, Bharat N.
朗格汉斯细胞组织细胞增生症（LCH）是一种众所周知但罕见的疾病，可发生在任何年龄，具有显著不同的临床特征：自我退行性、局限性、多器官、侵袭性或致命的结局。先天性LCH罕见，临床上常为良性。虽然LCH以朗格汉斯细胞的克隆性增殖为特征，但其病因尚不清楚。尽管BRAF V600E突变最近被确定为LCH病例中一种复发性遗传改变，但这种突变在LCH异质谱中的临床意义目前尚不清楚。我们研究了一例发生在新生儿男性的皮肤良性先天性LCH， 8年未复发。在组织病理学上，出生后切除的皮肤病变表现出典型的LCH的细胞学和免疫表型特征。BRAF基因外显子15的测序分析显示V600D突变，等位基因丰度为2530%，对应于突变等位基因的LCH细胞为半合子。BRAF v600e特异性聚合酶链反应阴性。我们的报告首次发现了LCH中罕见的变异BRAF V600D突变，并为组成型激活BRAF癌基因诱导的细胞衰老作为先天性良性LCH的一种退行机制提供了支持。此外，我们的临床病理研究结果首次证明，V600D突变也可以在没有紫外线照射的情况下发生，并且可以发生在临床良性增殖中，类似于V600E突变。在大量LCH患者中进行额外的临床病理研究可能对确定BRAF突变在LCH中的病理生理作用有价值。(c) 2012 Wiley期刊有限公司
Langerhans cell histiocytosis (LCH) is a well-known but rare disease that may occur at any age with markedly variable clinical features: self-regressive, localized, multiorgan, aggressive, or fatal outcome. Congenital LCH is rare and often clinically benign. While LCH is characterized by a clonal proliferation of Langerhans cells, its etiology is unknown. Although BRAF V600E mutations were recently identified as a recurrent genetic alteration in LCH cases, the clinical significance of this mutation within the heterogeneous spectrum of LCH is also currently unknown. We studied a cutaneous, benign form of congenital LCH that occurred in a newborn male, without recurrence for 8 years. Histopathologically, the skin lesion excised after birth showed the typical cytologic and immunophenotypic features of LCH. Sequencing analysis of Exon 15 of the BRAF gene revealed the V600D mutation, with an allelic abundance of 2530%, corresponding to the LCH cells being hemizygous for the mutant allele. BRAF V600E-specific polymerase chain reaction was negative. Our report is the first to identify the rare, variant BRAF V600D mutation in LCH, and provides support for constitutively activated BRAF oncogene-induced cell senescence as a mechanism of regression in congenital, benign LCH. Further, our clinicopathologic findings provide proof for the first time that the V600D mutation can also occur in the absence of ultraviolet light, and can occur in a clinically benign proliferation, similar to the V600E mutation. Additional clinicopathologic studies in larger numbers of LCH patients may be valuable to ascertain the pathophysiologic role of BRAF mutations in LCH. (c) 2012 Wiley Periodicals, Inc.