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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Author notes

This work was supported by the National Natural Science Foundation of China (Nos. 82141119 and 82070202), the Capital’s Funds for Health Improvement and Research (Nos. 2022-2-1141 and 2020-2-2093), the Beijing Natural Science Foundation (No. 7232058), the Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority (No. XTZD20180201), and Funding for Reform and Development of Beijing Municipal Health Commission.

Competing Interests

The authors have no relevant financial interest in the products or companies described in this article.

C-J Wang and Cui contributed equally to this work

Supplementary data