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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MSK Authors
  1. Mario E Lacouture
    276 Lacouture
  2. Neal Rosen
    366 Rosen
  3. David Solit
    440 Solit
  4. David Hyman
    194 Hyman
  5. Christopher Yongchul Park
    89 Park
  6. Barry Stephen Taylor
    144 Taylor
  7. Zhan Yao
    24 Yao
  8. Samuel Royden Briggs
    16 Briggs
  9. Eli Louis Diamond
    90 Diamond
  10. Jose T Baselga
    410 Baselga
  11. Eunhee Kim
    28 Kim
  12. Ahmet Dogan
    174 Dogan
  13. Jean- Baptiste Micol
    23 Micol
  14. Stanley Chun-Wei Lee
    32 Lee
  15. Benjamin Heath Durham
    63 Durham
  16. Yijun   Gao
    8 Gao