Title |
Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms
|
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Published in |
Cancer Discovery, February 2016
|
DOI | 10.1158/2159-8290.cd-15-0913 |
Pubmed ID | |
Authors |
Eli L Diamond, Benjamin H Durham, Julien Haroche, Zhan Yao, Jing Ma, Sameer A Parikh, Zhaoming Wang, John Choi, Eunhee Kim, Fleur Cohen-Aubart, Stanley Chun-Wei Lee, Yijun Gao, Jean-Baptiste Micol, Patrick Campbell, Michael P Walsh, Brooke Sylvester, Igor Dolgalev, Olga Aminova, Adriana Heguy, Paul Zappile, Joy Nakitandwe, Chezi Ganzel, James D Dalton, David W Ellison, Juvianee Estrada-Veras, Mario Lacouture, William A Gahl, Philip J Stephens, Vincent A Miller, Jeffrey S Ross, Siraj M Ali, Samuel R Briggs, Omotayo Fasan, Jared Block, Sebastien Héritier, Jean Donadieu, David B Solit, David M Hyman, José Baselga, Filip Janku, Barry S Taylor, Christopher Y Park, Zahir Amoura, Ahmet Dogan, Jean-Francois Emile, Neal Rosen, Tanja A Gruber, Omar Abdel-Wahab |
Abstract |
Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of BRAFV600E mutations in ~50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of BRAFV600E-wildtype, non-LCH patients 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 BRAFV600E-wildtype, non-LCH patients. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of MAP2K1- and ARAF-mutated, non-LCH patients using MEK and RAF inhibitors, respectively, resulted in clinical efficacy demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 3 | 38% |
Japan | 1 | 13% |
United Kingdom | 1 | 13% |
Unknown | 3 | 38% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 4 | 50% |
Practitioners (doctors, other healthcare professionals) | 2 | 25% |
Scientists | 1 | 13% |
Science communicators (journalists, bloggers, editors) | 1 | 13% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 186 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 32 | 17% |
Other | 25 | 13% |
Student > Ph. D. Student | 15 | 8% |
Student > Master | 15 | 8% |
Professor | 15 | 8% |
Other | 41 | 22% |
Unknown | 43 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 82 | 44% |
Biochemistry, Genetics and Molecular Biology | 20 | 11% |
Agricultural and Biological Sciences | 17 | 9% |
Immunology and Microbiology | 5 | 3% |
Engineering | 2 | 1% |
Other | 11 | 6% |
Unknown | 49 | 26% |