Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

组织细胞 朗格汉斯细胞组织细胞增多症 癌症研究 生物 组织细胞肉瘤 曲美替尼 组织细胞增多症 索拉非尼 突变 MAPK/ERK通路 医学 激酶 免疫学 基因 病理 遗传学 疾病 肝细胞癌
作者
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 E. Sylvester,Igor Dolgalev,Olga Aminova,Adriana Heguy,Paul Zappile,Joy Nakitandwe,Chezi Ganzel,James Dalton,David W. Ellison,Juvianee Estrada‐Veras,Mario E. Lacouture,William A. Gahl,Philip J. Stephens,Vincent A. Miller,Jeffrey S. Ross,Siraj M. Ali,Samuel Briggs,Omotayo Fasan,Jared Block,Sébastien Héritier,Jean Donadieu,David B. Solit,David M. Hyman,José Baselga,Filip Janků,Barry S. Taylor,Christopher Y. Park,Zahir Amoura,Ahmet Doğan,Jean François Emile,Neal Rosen,Tanja A. Grüber,Omar Abdel‐Wahab
出处
期刊:Cancer Discovery [American Association for Cancer Research]
卷期号:6 (2): 154-165 被引量:392
标识
DOI:10.1158/2159-8290.cd-15-0913
摘要

Abstract 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 BRAFV600E 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 BRAFV600E–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 BRAFV600E–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. Significance: 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. Cancer Discov; 6(2); 154–65. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109
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