Diverse and targetable kinase alterations drive histiocytic neoplasms Journal Article
| Authors: | Diamond, E. L.; Durham, B. H.; Haroche, J.; Yao, Z.; Ma, J.; Parikh, S. A.; Wang, Z.; Choi, J.; Kim, E.; Cohen-Aubart, F.; Lee, S. C. W.; Gao, Y.; Micol, J. B.; Campbell, P.; Walsh, M. P.; Sylvester, B.; Dolgalev, I.; Aminova, O.; Heguy, A.; Zappile, P.; Nakitandwe, J.; Ganzel, C.; Dalton, J. D.; Ellison, D. W.; Estrada-Veras, J.; Lacouture, M.; Gahl, W. A.; Stephens, P. J.; Miller, V. A.; Ross, J. S.; Ali, S. M.; Briggs, S. R.; Fasan, O.; Block, J.; Heritier, S.; Donadieu, J.; Solit, D. B.; Hyman, D. M.; Baselga, J.; Janku, F.; Taylor, B. S.; Park, C. Y.; Amoura, Z.; Dogan, A.; Emile, J. F.; Rosen, N.; Gruber, T. A.; Abdel-Wahab, O. |
| Article Title: | 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 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 fi rst 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. © 2015 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 6 |
| Issue: | 2 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2015-02-01 |
| Start Page: | 154 |
| End Page: | 165 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-15-0913 |
| PROVIDER: | scopus |
| PMCID: | PMC4744547 |
| PUBMED: | 26566875 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 March 2016 -- Source: Scopus |
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