Clinical study of MAP2K1-mutated Langerhans cell histiocytosis in children

Abstract

To analyze the genetic and clinical features of children with MAP2K1-mutated Langerhans cell histiocytosis (LCH). MethodsWe compared the clinical features of 37 children with MAP2K1-mutated LCH with those of the BRAF V600E mutation group (n = 133) and no known mutation group (n = 59) in the same period. ResultsWe 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 BRAF V600E 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 signi cant difference in clinical features compared with the no known mutation group. The 2-year progression-free survival rate of rst-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. ConclusionThe children with MAP2K1-mutated LCH have speci c clinical features requiring clinical strati cation and precise treatment. MAP2K1-mutated patients with lung involvement (especially with bony thorax involvement) had poor prognosis.

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

“…In 2010, Rollins and colleagues discovered recurrent somatic BRAF V600E mutations in LCH. 15 Subsequently, other groups confirmed the presence of BRAF V600E mutations in ∼50% to 60% of patients with LCH, 10 , 16 , 17 , 18 , 19 , 20 and identified alternative MAPK pathway–activating genetic alterations in patients without BRAF V600E ( supplemental Figure 2 ). 17 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 Most notably, somatic mutations in MAP2K1 exon 2 or 3 and small insertions and/or deletions (indels) in BRAF exon 12 were recurrently detected.…”

“…Our study confirms that MAP2K1 mutations in pediatric LCH predominantly occur in exon 2, affecting the αA-helix of MEK1 ( Figure 5 ; supplemental Figure 12 ), 66 , 67 with p.Q58_E62del as the most detected mutation ( supplemental Table 9 ). 19 The distinction between MAP2K1 exon 2 or 3 mutations is important because the mutations in exon 2 are RAF-regulated, whereas the deletions in exon 3 are RAF and phosphorylation independent. 68 Consequently, these MAP2K1 exon 3 deletions are less sensitive to allosteric MEK inhibitors, such as trametinib or cobimetinib.…”