Abstract
To analyze the genetic and clinical features of children with MAP2K1-mutated Langerhans cell histiocytosis (LCH). We compared the clinical features of 37 children with MAP2K1-mutated LCH with those of the BRAFV600E mutation group (n = 133) and no known mutation group (n = 59) in the same period. We found 13 mutations of the MAP2K1 gene, which were mainly concentrated at p.53-62 and p.98-103. The most common mutation site was c.172_186del (12/37). Compared with the BRAFV600E mutation group, the patients with MAP2K1 mutations were mainly characterized by single-system multiple bone involvement (P = 0.022), with later disease onset (P = 0.029) as well as less involvement of risk organs, especially liver (P = 0.024). There was no significant difference in clinical features compared with the no known mutation group. The 2-year progression-free survival rate of first-line treatment (ChiCTR1900025783, 07/09/2019) in MAP2K1-mutated patients was 65.6% ± 9.5%. The prognosis of patients with lung involvement was poor [HR (95% CI) = 6.312 (1.769-22.526), P = 0.005]. More progression or relapses could be found in patients with bony thorax involvement (8/17 vs. 2/20, P = 0.023), yet involvements in other sites of bones, such as craniofacial bone involvement (8/26 vs. 2/11, P = 0.688) and limb bone involvement (5/12 vs. 5/25, P = 0.240), were not correlated to disease progression or relapse. The children with MAP2K1-mutated LCH have specific clinical features requiring clinical stratification and precise treatment. MAP2K1-mutated patients with lung involvement (especially with bony thorax involvement) had poor prognosis.
Highlights
Langerhans cell histiocytosis (LCH) is a rare clonal disease characterized by the expansion of Langerhans cells derived from myeloid precursors and is more common in children than in adults (Allen et al 2018)
We found 13 mutations of the MAP2K1 gene, which were mainly concentrated at p.53–62 and p
Compared with the BRAFV600E mutation group, the patients with MAP2K1 mutations were mainly characterized by single system multiple bone involvement (P = 0.022), with later disease onset (P = 0.029) as well as less involvement of risk organs, especially liver (P = 0.024)
Summary
Langerhans cell histiocytosis (LCH) is a rare clonal disease characterized by the expansion of Langerhans cells derived from myeloid precursors and is more common in children than in adults (Allen et al 2018). Various clinical manifestations of LCH can be found with many systems involved, such as bone, skin, lung, liver, spleen etc. The prognosis of patients with risk organ (RO) involvement, including the liver, spleen and hematopoietic system, is generally poor. The risk of sequelae of the central nervous system (CNS) and disease reactivation is higher in patients with CNS-risk lesions (including craniofacial bone, eye, ear and oral involvement) (Chow et al 2017). BRAFV600E is the most common gene mutation, identified in more than 60% of LCH patients. MAP2K1 is another common mutant gene whose mutation frequency varies from 8.6% to 46% (Lian et al 2019). The activated coding product of the MAP2K1 gene, MAP2K1 kinase, can activate its downstream ERK kinase, which in turn affects the proliferation, differentiation and other functions of cells (Hayase et al 2020)
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