Longitudinal assessment of peripheral blood BRAFV600E levels in patients with Langerhans cell histiocytosis
Longitudinal assessment of peripheral blood BRAFV600E levels in patients with Langerhans cell histiocytosis
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DOI：
10.1038/s41390-018-0238-y
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发表时间：
2019-05-01
影响因子：
3.6
通讯作者：
Hurter, Caroline
中科院分区：
文献类型：
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作者：
Schwentner, Raphaela;Kolenova, Alexandra;Hurter, Caroline
背景：朗格汉斯细胞组织细胞增生症(LCH)是由髓系细胞中MAPK信号通路的结构性激活引起的一种组织细胞疾病。在50%-60%的病例中，它是由BRAFV600E突变引起的。有证据表明LCH患者外周血中BRAFV600E水平与疾病负担相关，可作为判断疾病程度和治疗反应的指标。然而，目前对于如何进行微小播散性疾病的检测还没有达成共识。方法：评估了确定LCH患者突变负荷的不同方法，并在化疗和/或RAF抑制剂维莫拉非尼治疗期间对患者DNA进行了纵向评估。从全血、不同白细胞亚群和循环中无细胞DNA(CCF-DNA)中提取DNA。结果：从全血中检测BRAF水平优于使用CCF-DNA。此外，重要的是确定临床相关的BRAF突变细胞亚群，如CD14(+)单核细胞或CD1c(+)树突状细胞，因为其他血细胞也可能含有突变，从而混淆全血或ccfDNA测量。结论：我们的数据支持RAF抑制剂单药治疗降低疾病活动性但不能治愈LCH的观点。
BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disorder driven by a constitutive activation of the MAPK signaling pathway in myeloid cells. In 50-60% of cases, it is caused by the BRAFV600E mutation. There is evidence that levels of BRAFV600E in the peripheral blood of patients with LCH correlate with disease burden and could be used as marker for disease extent and response to therapy. However, there is currently no consensus on how testing for minimal disseminated disease should be performed.METHODS: Different approaches to determine the mutation load in patients with LCH were assessed and longitudinal evaluation of patient DNA during treatment with chemotherapy and/or the RAF inhibitor vemurafenib was performed. DNA was isolated from whole blood, different leukocyte subsets, and circulating cell-free DNA (ccf-DNA).RESULTS: We show that determining BRAF levels from whole blood is superior to using ccfDNA. Furthermore, it is important to identify the clinically relevant BRAF-mutated cellular subpopulations such as CD14(+) monocytes or CD1c(+) DCs, since other blood cells can also harbor the mutation and therefore confound whole blood or ccfDNA measurements.CONCLUSION: Our data support the view that single-agent treatment with an RAF inhibitor reduces disease activity but does not cure LCH.