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
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
大模型应助吴剑宇采纳,获得10
1秒前
1秒前
小蘑菇应助随便吧采纳,获得10
2秒前
trust发布了新的文献求助10
2秒前
4秒前
5秒前
李哈哈发布了新的文献求助10
5秒前
科研通AI5应助cary采纳,获得10
5秒前
5秒前
威武雪兰完成签到,获得积分10
5秒前
6秒前
aktuell完成签到,获得积分10
6秒前
昵称完成签到,获得积分10
7秒前
077发布了新的文献求助10
8秒前
8秒前
赘婿应助熬夜的桃子采纳,获得10
8秒前
bkagyin应助单薄小蜜蜂采纳,获得30
8秒前
9秒前
胡建鹏完成签到 ,获得积分10
9秒前
DMPK完成签到,获得积分10
10秒前
10秒前
10秒前
ljhy发布了新的文献求助10
10秒前
sapphire完成签到,获得积分10
10秒前
脑洞疼应助zsgot3采纳,获得10
10秒前
10秒前
11秒前
trust完成签到,获得积分10
11秒前
彭于晏应助JXY采纳,获得10
11秒前
11秒前
Andrea发布了新的文献求助10
12秒前
12秒前
汉堡包应助申左一采纳,获得30
12秒前
亓大大发布了新的文献求助10
13秒前
NexusExplorer应助爱笑雨竹采纳,获得10
13秒前
13秒前
书瑶完成签到,获得积分10
13秒前
akaMZT完成签到,获得积分20
13秒前
量子星尘发布了新的文献求助10
13秒前
思源应助ljhy采纳,获得10
13秒前
高分求助中
计划经济时代的工厂管理与工人状况(1949-1966)——以郑州市国营工厂为例 500
INQUIRY-BASED PEDAGOGY TO SUPPORT STEM LEARNING AND 21ST CENTURY SKILLS: PREPARING NEW TEACHERS TO IMPLEMENT PROJECT AND PROBLEM-BASED LEARNING 500
The Pedagogical Leadership in the Early Years (PLEY) Quality Rating Scale 410
Stackable Smart Footwear Rack Using Infrared Sensor 300
Modern Britain, 1750 to the Present (第2版) 300
Writing to the Rhythm of Labor Cultural Politics of the Chinese Revolution, 1942–1976 300
Lightning Wires: The Telegraph and China's Technological Modernization, 1860-1890 250
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 纳米技术 计算机科学 内科学 化学工程 复合材料 物理化学 基因 催化作用 遗传学 冶金 电极 光电子学
热门帖子
关注 科研通微信公众号,转发送积分 4603700
求助须知:如何正确求助?哪些是违规求助? 4012310
关于积分的说明 12423171
捐赠科研通 3692797
什么是DOI,文献DOI怎么找? 2035913
邀请新用户注册赠送积分活动 1068997
科研通“疑难数据库(出版商)”最低求助积分说明 953482