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

• Published in: Genes chromosomes & cancer 2013-01, Vol.52 (1), p.99-106
• Main Authors: Kansal, Rina, Quintanilla-Martinez, Leticia, Datta, Vivekananda, Lopategui, Jean, Garshfield, Gary, Nathwani, Bharat N.
• Format: Article
• Language: English
• Subjects: Base Sequence; Exons; Histiocytosis, Langerhans-Cell - congenital; Histiocytosis, Langerhans-Cell - genetics; Histiocytosis, Langerhans-Cell - pathology; Histiocytosis, Langerhans-Cell - surgery; Humans; Immunohistochemistry; Infant, Newborn; Male; Molecular Sequence Data; Point Mutation; Polymerase Chain Reaction; Proto-Oncogene Proteins B-raf - genetics; Sequence Analysis, DNA; Skin Diseases - congenital; Skin Diseases - genetics; Skin Diseases - pathology; Skin Diseases - surgery
• ISSN: 1045-2257; 1098-2264
• DOI: 10.1002/gcc.22010

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. © 2012 Wiley Periodicals, Inc.