Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	6	2	2016 Feb	154-65	Cancer Discov

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
MAP2K1	D65N	missense	gain of function - predicted	MAP2K1 D65N does not lie within any known functional domains 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 in culture (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 in culture (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, Nov 2023).
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, Mar 2024).
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 in culture (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 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
MAP2K1 Q56P	Erdheim-Chester disease	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