Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis

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

doi:10.5858/arpa.2023-0236-OA

Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis

Arch Pathol Lab Med. 2024 May 16. doi: 10.5858/arpa.2023-0236-OA. Online ahead of print.

Authors

Chan-Juan Wang^{1

2

3

4}, Lei Cui^{1

2

3

4}, Shuang-Shuang Li⁵, Hong-Hao Ma^{2

3

4}, Dong Wang^{2

3

4}, Hong-Yun Lian^{2

3

4}, Yun-Ze Zhao^{2

3

4}, Li-Ping Zhang^{2

3

4}, Wei-Jing Li^{1

2

3

4}, Qing Zhang^{1

2

3

4}, Xiao-Xi Zhao^{1

2

3

4}, Ying Yang^{2

3

4}, Xiao-Tong Huang^{1

2

3

4}, Wei Liu⁶, Yi-Zhuo Wang⁷, Wan-Shui Wu⁸, Tian-You Wang^{2

3

4}, Rui Zhang^{2

3

4}, Zhi-Gang Li^{1

2

3

4}

Affiliations

¹ From the Laboratory of Hematologic Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China; (C-J Wang, Cui, W-J Li, Q Zhang, X-X Zhao, Huang, Z-G Li).
² From the Laboratory of Hematologic Diseases, Beijing Key Laboratory of Pediatric Hematology Oncology, Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China (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).
³ National Key Discipline of Pediatrics, Capital Medical University, Beijing, China (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).
⁴ Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China (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).
⁵ MyGenostics Inc, Beijing, China (S-S Li).
⁶ the Department of Hematology Oncology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, China (Liu).
⁷ the Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China (Y-Z Wang).
⁸ the Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, Beijing, China (Wu).

PMID: 38749502
DOI: 10.5858/arpa.2023-0236-OA

Abstract

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.