Transcriptomics

Dataset Information

299

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms


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. 13 patient samples were analyzed by RNA-seq and had 2 replicates.

ORGANISM(S): Homo sapiens  

SUBMITTER: Omar Abdel-Wahab   Igor Dolgalev 

PROVIDER: E-GEOD-74442 | ArrayExpress | 2015-11-11

SECONDARY ACCESSION(S): SRP065445GSE74442PRJNA300424

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms.

Diamond Eli L EL   Durham Benjamin H BH   Haroche Julien J   Yao Zhan Z   Ma Jing J   Parikh Sameer A SA   Wang Zhaoming Z   Choi John J   Kim Eunhee E   Cohen-Aubart Fleur F   Lee Stanley Chun-Wei SC   Gao Yijun Y   Micol Jean-Baptiste JB   Campbell Patrick P   Walsh Michael P MP   Sylvester Brooke B   Dolgalev Igor I   Aminova Olga O   Heguy Adriana A   Zappile Paul P   Nakitandwe Joy J   Ganzel Chezi C   Dalton James D JD   Ellison David W DW   Estrada-Veras Juvianee J   Lacouture Mario M   Gahl William A WA   Stephens Philip J PJ   Miller Vincent A VA   Ross Jeffrey S JS   Ali Siraj M SM   Briggs Samuel R SR   Fasan Omotayo O   Block Jared J   Héritier Sebastien S   Donadieu Jean J   Solit David B DB   Hyman David M DM   Baselga José J   Janku Filip F   Taylor Barry S BS   Park Christopher Y CY   Amoura Zahir Z   Dogan Ahmet A   Emile Jean-Francois JF   Rosen Neal N   Gruber Tanja A TA   Abdel-Wahab Omar O  

Cancer discovery 20151113 2


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 ar  ...[more]

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