Frequent KIT mutations in skin lesions of patients with BRAF wild-type Langerhans cell histiocytosis
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BRIEF REPORT
Frequent KIT mutations in skin lesions of patients with BRAF wild-type Langerhans cell histiocytosis Béla Tóth 1 & Norbert Kiss 1 & Judit Hársing 1 & Sarolta Kárpáti 1 & Judit Csomor 2 & Csaba Bödör 2 & József Tímár 3 & Erzsébet Rásó 3 Received: 10 December 2019 / Revised: 30 March 2020 / Accepted: 19 April 2020 # The Author(s) 2020
Abstract Langerhans cell histiocytosis (LCH) is characterized by mutations of the RAS-RAF-MAPK signaling pathway. We analyzed MAP2K1, NRAS and KIT mutation incidence in skin lesions of BRAF wild-type (wt) LCH patients. We evaluated the occurrence of MAP2K1, NRAS and KIT mutations in seven LCH and one indeterminate cell histiocytosis (ICH) patients. MAP2K1 mutation frequency was found to be 3/7 (42.9%) in LCH and also found in ICH. Similarly, the KIT mutation frequency was found to be equally prevalent (4/7, 57.1%) in LCH and also occurred in ICH. Involvement of KIT exons in LCH-ICH indicated that exon 9/11/18 were equally prevalent followed by exon 13. This exploratory analysis on BRAF-wt LCH revealed a KIT mutation rate comparable to MAP2K1. Although the detected KIT mutations are different from activating mutations found in other KITdependent neoplasms, our data suggest that KIT-inhibitors might have a role in treating BRAF-wt LCH patients. Keywords Langerhans cell histiocytosis . BRAF . MAP2K1 . NRAS . KIT
Introduction The revised classification scheme of the Histiocyte Society classified histiocytic disorders into five groups. Group L (Langerhans) includes Langerhans cell histiocytosis (LCH), indeterminate cell histiocytosis (ICH), Erdheim-Chester disease (ECD) and mixed LCH/ECD [1]. The incidence of LCH, which is the most common histiocytic disease, is estimated to be between 4.6 and 9 cases per million children, while it is 1–2 cases per million adults [2]. The most frequent mutational driver in L type histocytoses is BRAF, which rarely affects ARAF. This is followed by frequent mutations of MAP2K1
(rarely MAP3K1). Mutations rarely affect RAS itself (N- or H-) or the AKT-mTOR signaling pathway [1, 2]. Different therapeutic strategies are used for the treatment of histiocytosis, usually resulting in an excellent control of the localized disease, but the multifocal or systemic disease can be refractory to contemporary therapies [3]. BRAF inhibitors have been successfully tested in LCH [4]. Since the protein expression of c-KIT was accidentally demonstrated in LCH, this prompted clinical studies. While KIT-inhibitor imatinib mesylate was successfully used in certain cases of LCH [5], KIT mutations have not been demonstrated in the skin lesions. Accordingly, our aim was to analyze KIT mutations in skin lesions of patients with LCH carrying wild-type (wt) BRAF.
This article is part of the Topical Collection on Quality in Pathology
Methods * Béla Tóth [email protected] 1
Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, 41 Mária utca, Budapest H-1085, Hungary
2
1st Department of Pathology and Experimental Cancer Research, Semme
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