朗格汉斯细胞组织细胞增生症患儿的遗传特征及其预后影响

Chan-Juan Wang, Lei Cui, Shuang-Shuang Li, Hong-Hao Ma, Dong Wang, Hong-Yun Lian, Yun-Ze Zhao, Li-Ping Zhang, Wei-Jing Li, Qing Zhang, Xiao-Xi Zhao, Ying Yang, Xiao-Tong Huang, Wei Liu, Yi-Zhuo Wang, Wan-Shui Wu, Tian-You Wang, Rui Zhang, Zhi-Gang Li
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引用次数: 0

摘要

背景朗格汉斯细胞组织细胞增生症(Langerhans cell histiocytosis,LCH)是一种罕见的髓细胞肿瘤,主要累及幼儿:研究小儿 LCH 的基因改变及其与临床特征和预后的相关性:我们对儿科患者的LCH病变进行了靶向测序,以检测基因突变:223例患者中有187例(83.9%)发现了MAPK通路5个基因中的30个基因组改变。BRAF V600E(B-Raf 原癌基因,丝氨酸/苏氨酸激酶)是最常见的突变(51.6%),其次是 MAP2K1(丝裂原活化蛋白激酶激酶 1)改变(17.0%)和其他 BRAF 突变(13.0%)。ARAF(A-Raf 原癌基因,丝氨酸/苏氨酸激酶)和 KRAS(KRAS 原癌基因,GTPase)突变相对罕见(分别为 2.2% 和 0.9%)。此外,还发现 FNBP1(甲形蛋白结合蛋白 1)::BRAF 融合和 MAP3K10(丝裂原活化蛋白激酶激酶 10)突变 A17T 和 R823C 各 1 例,可能构成性激活 ERK1/2 磷酸化。BRAF V600E在危险器官受累的患者中更为常见,而MAP2K1突变在单系统LCH患者中更为普遍(P = .001)。BRAF V600E与颅面部骨骼、皮肤、肝脏、脾脏和耳朵受累有关(所有P < .05)。其他BRAF基因突变的患者脊柱受累的比例更高(P = .006)。单变量分析显示,在接受一线治疗的患者中,4个分子亚组的无进展生存期存在显著差异(P = .02)。多变量分析显示,危险器官受累是最强的独立不良预后因素(危险比为8.854;P < .001);BRAF或MAP2K1突变不是独立的预后因素:结论:大多数儿童LCH患者都携带涉及MAPK通路的体细胞突变,这与临床特征和一线化疗的结果相关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.

Context.—: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.

Objective.—: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH.

Design.—: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients.

Results.—: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor.

Conclusions.—: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

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