Identification of the V600D mutation in Exon 15 of the BRAF oncogene in congenital, benign langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is a well-known but rare disease that may occur at any age with markedly variable clinical features: self-regressive, localized, multiorgan, aggressive, or fatal outcome. Congenital LCH is rare and often clinically benign. While LCH is characterized by a clonal proliferation of Langerhans cells, its etiology is unknown. Although BRAF V600E mutations were recently identified as a recurrent genetic alteration in LCH cases, the clinical significance of this mutation within the heterogeneous spectrum of LCH is also currently unknown. We studied a cutaneous, benign form of congenital LCH that occurred in a newborn male, without recurrence for 8 years. Histopathologically, the skin lesion excised after birth showed the typical cytologic and immunophenotypic features of LCH. Sequencing analysis of Exon 15 of the BRAF gene revealed the V600D mutation, with an allelic abundance of 25-30%, corresponding to the LCH cells being hemizygous for the mutant allele. BRAF V600E-specific polymerase chain reaction was negative. Our report is the first to identify the rare, variant BRAF V600D mutation in LCH, and provides support for constitutively activated BRAF oncogene-induced cell senescence as a mechanism of regression in congenital, benign LCH. Further, our clinicopathologic findings provide proof for the first time that the V600D mutation can also occur in the absence of ultraviolet light, and can occur in a clinically benign proliferation, similar to the V600E mutation. Additional clinicopathologic studies in larger numbers of LCH patients may be valuable to ascertain the pathophysiologic role of BRAF mutations in LCH.

Somatic activating ARAF mutations in Langerhans cell histiocytosis

“…Two additional somatic BRAF mutations have been observed in LCH that also activate the kinase: BRAF 600DLAT (an insertional mutant) 7 and V600D, which occurs in melanoma. 6 The ARAF mutations in the sample from patient 1 provide an unexpected and novel mechanism for ERK pathway activation.…”

“…4 The discovery of somatic activating BRAF mutations-in particular, but not exclusively, BRAF V600E-in 50% to 60% of patients with LCH has brought the promise of targeted therapeutics to these patients. [5][6][7][8] A recent report describes clinical responses to vemurafenib, a BRAF inhibitor, in patients with a mixture of LCH and Erdheim-Chester disease, 9 another disorder associated with BRAF V600E, 10 suggesting that BRAF V600E is a driver mutation in LCH. However, the extracellular signal-regulated kinase (ERK) signaling pathway is activated in pathologic histiocytes of all LCH patients including those with wild-type BRAF alleles.…”

Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis

“…1,[4][5][6][7] Although there have been case reports of other BRAF mutations (both somatic and germ line) in LCH patients as well as compound somatic ARAF mutations identified in a single patient, no recurrent mutations other than BRAFV600E were previously reported in LCH. 7,29,30 A major finding of this study is the identification of recurrent activating somatic mutations in MAP2K1, the gene encoding MEK1 (a core MAPK pathway member downstream of BRAF), in patients with LCH. Somatic activating MAP2K1 mutations are rarer in human cancers than BRAF mutations but typically arise in the same spectrum of tumor types.…”

Detection of BRAF V600E Mutation in Langerhans Cell Histiocytosis Using High-resolution Melting Analysis in Decalcified, Paraffin-embedded Tissue

“…Since over half of the LCH patient population carries this mutation, our rapid assay can serve as a screening test to identify these patients in a timely manner, with higher sensitivity and lower cost than with sequencing. If clinically necessary, patients with negative screening test results may be further tested by different assays for other BRAF mutations that are relatively rare in LCH [4,8].…”