The clinical significance of the BRAFV600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary Langerhans cell histiocytosis (PLCH), is not well understood. Similarly, the spectrum of molecular alterations involved in adult LCH has not been fully delineated. To address these issues, we genotyped a large number of adult LCH biopsies and searched for an association of identified molecular alterations with clinical presentation and disease outcome. Biopsies from 117 adult LCH patients, 83 with PLCH (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAFV600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression. MAPK pathway alterations were detected in 59 out of 69 cases (86%) (BRAFV600E mutation: 36%, BRAFN486_P490 deletion: 28%, MAP2K1 mutations: 15%, isolated NRASQ61 mutations: 4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAFV600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAFV600E status did not influence the risk of LCH progression over time. Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike reports in paediatric LCH, BRAFV600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH. MAPK alterations are present in most lesions from adult pulmonary LCH patients. In patients with refractory progressive disease, the identification of these alterations, including BRAF deletions, is important to guide the choice of targeted treatment. http://bit.ly/2Qoknsn

中文翻译：

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成人朗格汉斯细胞组织细胞增生症伴肺受累的遗传景观

BRAFV600E 突变在成人朗格汉斯细胞组织细胞增生症 (LCH) 中的临床意义尚不清楚，包括肺朗格汉斯细胞组织细胞增生症 (PLCH)。同样，成人 LCH 中涉及的分子改变谱尚未完全描绘。为了解决这些问题，我们对大量成人 LCH 活检进行了基因分型，并寻找已确定的分子改变与临床表现和疾病结果的关联。对来自 117 名成年 LCH 患者的活检，其中 83 名患有 PLCH（中位年龄 36.4 岁，56 名女性，38 名多系统疾病，79 名单系统疾病，65 名当前吸烟者）对 BRAFV600E 突变进行基因分型。在 69 例中，LCH 病变也通过全外显子组测序 (WES) 或靶向基因组下一代测序 (NGS) 进行基因分型。Cox 模型用于估计基线特征与 LCH 进展风险的关联。在 69 例病例中的 59 例 (86%) 中检测到 MAPK 通路改变（BRAFV600E 突变：36%，BRAFN486_P490 缺失：28%，MAP2K1 突变：15%，孤立的 NRASQ61 突变：4%），而在 PLCH 中几乎不存在 KRAS 突变病变。在 PLCH 患者中，BRAFV600E 突变与诊断时的 LCH 表现无关，包括吸烟状况和肺功能。BRAFV600E 状态不影响 LCH 随时间进展的风险。因此，MAPK 改变存在于成人 LCH 患者的大多数病变中，尤其是 PLCH。与儿科 LCH 的报告不同，BRAFV600E 基因分型没有提供关于疾病结果的额外信息。寻找涉及 MAPK 途径的改变，包括 BRAF 缺失，可用于指导选定的难治性进行性 LCH 患者的靶向治疗。MAPK 改变存在于成人肺 LCH 患者的大多数病变中。在难治性进行性疾病患者中，识别这些改变，包括 BRAF 缺失，对于指导靶向治疗的选择很重要。http://bit.ly/2Qoknsn