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Ref Type Journal Article
PMID (26566875)
Authors Diamond EL, Durham BH, Haroche J, Yao Z, Ma J, Parikh SA, Wang Z, Choi J, Kim E, Cohen-Aubart F, Lee SC, Gao Y, Micol JB, Campbell P, Walsh MP, Sylvester B, Dolgalev I, Aminova O, Heguy A, Zappile P, Nakitandwe J, Ganzel C, Dalton JD, Ellison DW, Estrada-Veras J, Lacouture M, Gahl WA, Stephens PJ, Miller VA, Ross JS, Ali SM, Briggs SR, Fasan O, Block J, Héritier S, Donadieu J, Solit DB, Hyman DM, Baselga J, Janku F, Taylor BS, Park CY, Amoura Z, Dogan A, Emile JF, Rosen N, Gruber TA, Abdel-Wahab O
Title Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms.
Journal Cancer discovery
Vol 6
Issue 2
Date 2016 Feb
URL
Abstract Text Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
MAP2K1 D65N missense gain of function - predicted MAP2K1 D65N lies adjacent to the protein kinase domain of the Map2k1 protein (UniProt.org). D65N is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased Mek phosphorylation relative to wild-type Map2k1 (PMID: 26566875).
MAP2K1 E120Q missense gain of function - predicted MAP2K1 E120Q lies within the protein kinase domain of the Map2k1 protein (UniProt.org). E120Q is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased Mek phosphorylation relative to wild-type Map2k1 (PMID: 26566875).
MAP2K1 E144K missense gain of function MAP2K1 E144K lies within the protein kinase domain of the Map2k1 protein (UniProt.org). E144K confers a gain of function to the Map2k1 protein as demonstrated by increased Mek and Erk phosphorylation relative to wild-type Map2k1 (PMID: 26566875).
MAP2K1 F53_Q58del deletion gain of function MAP2K1 F53_Q58del results in the deletion of six amino acids in the Map2k1 protein from amino acids 53 to 58 (UniProt.org). F53_Q58del results in activation of Map2k1 as indicated by increased Erk and Mek phosphorylation in cell culture (PMID: 26566875, PMID: 29483135).
MAP2K1 F68L missense unknown MAP2K1 F68L lies within the protein kinase domain of the Map2k1 protein (UniProt.org). F68L has been identified in the scientific literature (PMID: 26566875), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Sep 2020).
MAP2K1 L37P missense gain of function MAP2K1 L37P lies within the nuclear export region of the Map2k1 protein (PMID: 26566875). L37P confers a gain of function to the Map2k1 protein as demonstrated by increased Mek and Erk phosphorylation relative to wild-type Map2k1 (PMID: 26566875).
MAP2K1 Q58_E62del deletion gain of function MAP2K1 Q58_E62del results in the deletion of five amino acids in the Map2k1 protein from amino acis 58 to 62 (UniProt.org). Q58_E62del confers a gain of function to the Map2k1 protein as demonstrated by increased Mek and Erk phosphorylation relative to wild-type Map2k1 (PMID: 26566875, PMID: 25202140, PMID: 28935960).
MAP2K1 S123P missense unknown MAP2K1 S123P lies within the protein kinase domain of the Map2k1 protein (UniProt.org). S123P has been identified in the scientific literature (PMID: 26566875), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Aug 2020).
MAP2K1 S123T missense gain of function MAP2K1 S123T lies within the protein kinase domain of the Map2k1 protein (UniProt.org). S123T confers a gain of function to the Map2k1 protein as demonstrated by increased Mek and Erk phosphorylation relative to wild-type Map2k1 (PMID: 26566875).
MAP2K1 T28I missense gain of function - predicted MAP2K1 T28I lies within the Erk binding domain of the Map2k1 protein (PMID: 26566875). T28I is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased Mek phosphorylation relative to wild-type Map2k1 (PMID: 26566875).
MAP2K1 V60M missense gain of function MAP2K1 V60M does not lie within any known functional domains of the Map2k1 protein (UniProt.org). V60M confers a gain of function to the Map2k1 protein as demonstrated by increased Mek and Erk phosphorylation relative to wild-type Map2k1 (PMID: 26566875).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 Q56P lymphatic system cancer predicted - sensitive Cobimetinib Case Reports/Case Series Actionable In a clinical case study, a patient with refractory Erdheim-Chester disease harboring a MAP2K1 Q56P mutation had a reduction of lymphatic infiltrates to background within a month of receiving Cotellic (cobimetinib) therapy (PMID: 26566875). 26566875
MAP2K1 K57N lymphatic system cancer sensitive Trametinib Case Reports/Case Series Actionable In a clinical case study, a patient with refractory Erdheim-Chester disease harboring a MAP2K1 K57N mutation had a sustained clinical response to Mekinist (trametinib) for over 6 months (PMID: 26566875). 26566875