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Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis
Chan-Juan Wang1,2,3, Lei Cui1,2,3, Shuang-Shuang Li4
1From the Laboratory of Hematologic Diseases, Beijing Pediatric Research Institute (C-J Wang, Cui, W-J Li, Q Zhang, X-X Zhao, Huang, Z-G Li) and Beijing Key Laboratory of Pediatric Hematology Oncology, Hematology Center (C-J Wang, Cui, Ma, D Wang, Lian, Y-Z Zhao, L-P Zhang, W-J Li, Q Zhang, X-X Zhao, Yang, Huang, T-Y Wang, R Zhang, Z-G Li), Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
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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