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      A novel fusion gene PLEKHA6‐NTRK3 in langerhans cell histiocytosis

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          Abstract

          Langerhans cell histiocytosis (LCH) is the most common histiocytosis with constitutive activation of the RAS–RAF–MEK–ERK (MAPKinase) cell signaling pathway. We analyzed 89 cases of BRAF and MAP2K1 mutations by Sanger sequencing, of which 18 cases showed that these two gene mutations are negative. Whole genome sequencing of suitable specimens in these negative cases revealed a translocation from the 3 intron of PLEKHA6 to the 13 intron of NTRK3 in one case. We identified that this translocation could cause a novel fusion mutation, PLEKHA6‐NTRK3. Overexpression of the PLEKHA6‐NTRK3 mutant in NIH 3T3 cells enhanced MAPKinase pathway activation, promote cell growth. Our result suggested that a new mutation need be included in LCH molecular screening panel to better define its prevalence in LCH.

          Abstract

          What's new?

          Langerhans cell histiocytosis (LCH) is a rare immune and neoplastic disorder. While it is known as the most common histiocytosis with constitutive activation of the RAS‐RAF‐MEK‐ERK (MAPKinase) cell signaling pathway, its pathogenesis remains obscure. Here, whole‐genome sequencing of BRAF V600E‐negative and MAP2K1‐negative LCH cases revealed a translocation from the intron 3 of PLEKHA6 to the intron 13 of NTRK3 in one patient, identifying a novel fusion mutation. Overexpression of PLEKHA6‐NTRK3 in vitro enhanced MAPKinase pathway activation, promoting cell growth. The results support the inclusion of the fusion mutation in LCH molecular screening panel to better define its prevalence in patients.

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          Most cited references29

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          A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma.

          Congenital (or infantile) fibrosarcoma (CFS) is a malignant tumour of fibroblasts that occurs in patients aged two years or younger. CFS is unique among human sarcomas in that it has an excellent prognosis and very low metastatic rate. CFS is histologically identical to adult-type fibrosarcoma (ATFS); however, ATFS is an aggressive malignancy of adults and older children that has a poor prognosis. We report a novel recurrent t(12;15)(p13;q25) rearrangement in CFS that may underlie the distinctive biological properties of this tumour. By cloning the chromosome breakpoints, we show that the rearrangement fuses the ETV6 (also known as TEL) gene from 12p13 with the 15q25 NTRK3 neurotrophin-3 receptor gene (also known as TRKC). Analysis of mRNA revealed the expression of ETV6-NTRK3 chimaeric transcripts in all three CFS tumours analysed. These were not detected in ATFS or infantile fibromatosis (IFB), a histologically similar but benign fibroblastic proliferation occurring in the same age-group as CFS. ETV6-NTRK3 fusion transcripts encode the helix-loop-helix (HLH) protein dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. Our studies indicate that a chimaeric PTK is expressed in CFS and this may contribute to oncogenesis by dysregulation of NTRK3 signal transduction pathways. Moreover, ETV6-NTRK3 gene fusions provide a potential diagnostic marker for CFS.
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            Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.

            Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography [PET], computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.
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              Targeting the RAF-MEK-ERK pathway in cancer therapy.

              The clinical success of selective kinase inhibitors, such as imatinib and erlotinib, as therapeutic agents for several human cancers has prompted substantial interest in the further development and clinical testing of such inhibitors for a wide variety of malignancies. While much of this effort has been focused on the receptor tyrosine kinases, including EGFR, HER2, PDGF receptor, c-KIT, and MET, inhibitors of serine/threonine kinases are also beginning to emerge within discovery pipelines. Among these kinases, the RAF and MEK kinases have received substantial attention, owing largely to the relatively high frequency of activating mutations of RAS ( approximately 20% of all human cancers), an upstream activator of the well established RAF-MEK-ERK signaling cascade, as well as frequent activating mutations in the BRAF kinase ( approximately 7% of all human cancers). Here, we summarize the current state of development of kinase inhibitors directed at this signaling pathway, a few of which have already demonstrating favorable toxicity profiles as well as promising activity in early phase clinical studies.
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                Author and article information

                Contributors
                liyanxin@scmc.com.cn
                shenshuhong@scmc.com.cn
                Journal
                Int J Cancer
                Int. J. Cancer
                10.1002/(ISSN)1097-0215
                IJC
                International Journal of Cancer
                John Wiley & Sons, Inc. (Hoboken, USA )
                0020-7136
                1097-0215
                26 October 2018
                01 January 2019
                : 144
                : 1 ( doiID: 10.1002/ijc.v144.1 )
                : 117-124
                Affiliations
                [ 1 ] Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology & Oncology Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University Shanghai 200127 China
                [ 2 ] Department of Pathology, Shanghai Children's Medical Center School of Medicine, Shanghai Jiao Tong University Shanghai 200127 China
                Author notes
                [*] [* ] Correspondence to: Shuhong Shen, Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology & Oncology, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China, Tel.: 86‐21‐38626297, Fax: 86‐21‐38626297, E‐mail: shenshuhong@ 123456scmc.com.cn ; or Yanxin Li, Tel.: 86‐21‐38626295, Fax: 86‐21‐68383916, E‐mail: liyanxin@ 123456scmc.com.cn
                Author information
                https://orcid.org/0000-0003-1055-5029
                Article
                IJC31636
                10.1002/ijc.31636
                6587734
                30098202
                074847b4-52ed-4400-b8be-b9a2479e40d2
                © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 26 March 2018
                : 17 May 2018
                : 25 May 2018
                Page count
                Figures: 4, Tables: 1, Pages: 8, Words: 4386
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 3067088381270623
                Award ID: 81772663
                Award ID: 8147031581670136
                Award ID: 81470315
                Award ID: 81772663
                Award ID: 81670136
                Award ID: 30670883
                Award ID: 81270623
                Award ID: 81470315
                Award ID: 81772663
                Award ID: 81670136
                Award ID: 30670883
                Award ID: 81270623
                Funded by: Collaborative Innovation Center for Translation Medicine at Shanghai Jiao Tong University School of Medicine
                Funded by: Shanghai Jiao Tong University School of Medical Engineering Cross Fund
                Funded by: The Science and Technology Commission of Shanghai Municipality
                Award ID: 14411950600
                Funded by: Collaborative Innovation Center for Translation Medicine at Shanghai Jiao Tong University School of Medicine
                Award ID: TM201502
                Funded by: Shanghai Jiao Tong University School of Medical Engineering Cross Fund
                Award ID: YG2017MS32
                Categories
                Molecular Cancer Biology
                Molecular Cancer Biology
                Custom metadata
                2.0
                ijc31636
                1 January 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:21.06.2019

                Oncology & Radiotherapy
                plekha6‐ntrk3,langerhans cell histiocytosis,fusion mutation,erk pathway

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