Diverse and targetable kinase alterations drive histiocytic neoplasms

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 Sylvester, Igor Dolgalev, Olga Aminova, Adriana Heguy, Paul ZappileJoy Nakitandwe, Chezi Ganzel, James D. Dalton, David W. Ellison, Juvianee Estrada-Veras, Mario Lacouture, William A. Gahl, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, Siraj M. Ali, Samuel R. Briggs, Omotayo Fasan, Jared Block, Sebastien Heritier, Jean Donadieu, David B. Solit, David M. Hyman, Jose Baselga, Filip Janku, Barry S. Taylor, Christopher Y. Park, Zahir Amoura, Ahmet Dogan, Jean Francois Emile, Neal Rosen, Tanja A. Gruber, Omar Abdel-Wahab

Research output: Contribution to journalArticle

135 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)154-165
Number of pages12
JournalCancer Discovery
Volume6
Issue number2
DOIs
StatePublished - Feb 1 2016

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Non-Langerhans-Cell Histiocytosis
Phosphotransferases
Mutation
Histiocytosis
Mitogen-Activated Protein Kinase Kinases
Neoplasms
Exome
Langerhans Cell Histiocytosis
Hematologic Neoplasms
Transcriptome
Dendritic Cells
Monocytes
Macrophages
Therapeutics
Genes

ASJC Scopus subject areas

  • Oncology

Cite this

Diamond, E. L., Durham, B. H., Haroche, J., Yao, Z., Ma, J., Parikh, S. A., ... Abdel-Wahab, O. (2016). Diverse and targetable kinase alterations drive histiocytic neoplasms. Cancer Discovery, 6(2), 154-165. https://doi.org/10.1158/2159-8290.CD-15-0913

Diverse and targetable kinase alterations drive histiocytic neoplasms. / Diamond, Eli L.; Durham, Benjamin H.; Haroche, Julien; Yao, Zhan; Ma, Jing; Parikh, Sameer A; Wang, Zhaoming; Choi, John; Kim, Eunhee; Cohen-Aubart, Fleur; Lee, Stanley Chun Wei; Gao, Yijun; Micol, Jean Baptiste; Campbell, Patrick; Walsh, Michael P.; Sylvester, Brooke; Dolgalev, Igor; Aminova, Olga; Heguy, Adriana; Zappile, Paul; Nakitandwe, Joy; Ganzel, Chezi; Dalton, James D.; Ellison, David W.; Estrada-Veras, Juvianee; Lacouture, Mario; Gahl, William A.; Stephens, Philip J.; Miller, Vincent A.; Ross, Jeffrey S.; Ali, Siraj M.; Briggs, Samuel R.; Fasan, Omotayo; Block, Jared; Heritier, Sebastien; Donadieu, Jean; Solit, David B.; Hyman, David M.; Baselga, Jose; Janku, Filip; Taylor, Barry S.; Park, Christopher Y.; Amoura, Zahir; Dogan, Ahmet; Emile, Jean Francois; Rosen, Neal; Gruber, Tanja A.; Abdel-Wahab, Omar.

In: Cancer Discovery, Vol. 6, No. 2, 01.02.2016, p. 154-165.

Research output: Contribution to journalArticle

Diamond, EL, Durham, BH, Haroche, J, Yao, Z, Ma, J, Parikh, SA, Wang, Z, Choi, J, Kim, E, Cohen-Aubart, F, Lee, SCW, Gao, Y, Micol, JB, Campbell, P, Walsh, MP, Sylvester, B, Dolgalev, I, Aminova, O, Heguy, A, Zappile, P, Nakitandwe, J, Ganzel, C, Dalton, JD, Ellison, DW, Estrada-Veras, J, Lacouture, M, Gahl, WA, Stephens, PJ, Miller, VA, Ross, JS, Ali, SM, Briggs, SR, Fasan, O, Block, J, Heritier, S, Donadieu, J, Solit, DB, Hyman, DM, Baselga, J, Janku, F, Taylor, BS, Park, CY, Amoura, Z, Dogan, A, Emile, JF, Rosen, N, Gruber, TA & Abdel-Wahab, O 2016, 'Diverse and targetable kinase alterations drive histiocytic neoplasms', Cancer Discovery, vol. 6, no. 2, pp. 154-165. https://doi.org/10.1158/2159-8290.CD-15-0913
Diamond, Eli L. ; Durham, Benjamin H. ; Haroche, Julien ; Yao, Zhan ; Ma, Jing ; Parikh, Sameer A ; Wang, Zhaoming ; Choi, John ; Kim, Eunhee ; Cohen-Aubart, Fleur ; Lee, Stanley Chun Wei ; Gao, Yijun ; Micol, Jean Baptiste ; Campbell, Patrick ; Walsh, Michael P. ; Sylvester, Brooke ; Dolgalev, Igor ; Aminova, Olga ; Heguy, Adriana ; Zappile, Paul ; Nakitandwe, Joy ; Ganzel, Chezi ; Dalton, James D. ; Ellison, David W. ; Estrada-Veras, Juvianee ; Lacouture, Mario ; Gahl, William A. ; Stephens, Philip J. ; Miller, Vincent A. ; Ross, Jeffrey S. ; Ali, Siraj M. ; Briggs, Samuel R. ; Fasan, Omotayo ; Block, Jared ; Heritier, Sebastien ; Donadieu, Jean ; Solit, David B. ; Hyman, David M. ; Baselga, Jose ; Janku, Filip ; Taylor, Barry S. ; Park, Christopher Y. ; Amoura, Zahir ; Dogan, Ahmet ; Emile, Jean Francois ; Rosen, Neal ; Gruber, Tanja A. ; Abdel-Wahab, Omar. / Diverse and targetable kinase alterations drive histiocytic neoplasms. In: Cancer Discovery. 2016 ; Vol. 6, No. 2. pp. 154-165.
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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.",
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AU - Diamond, Eli L.

AU - Durham, Benjamin H.

AU - Haroche, Julien

AU - Yao, Zhan

AU - Ma, Jing

AU - Parikh, Sameer A

AU - Wang, Zhaoming

AU - Choi, John

AU - Kim, Eunhee

AU - Cohen-Aubart, Fleur

AU - Lee, Stanley Chun Wei

AU - Gao, Yijun

AU - Micol, Jean Baptiste

AU - Campbell, Patrick

AU - Walsh, Michael P.

AU - Sylvester, Brooke

AU - Dolgalev, Igor

AU - Aminova, Olga

AU - Heguy, Adriana

AU - Zappile, Paul

AU - Nakitandwe, Joy

AU - Ganzel, Chezi

AU - Dalton, James D.

AU - Ellison, David W.

AU - Estrada-Veras, Juvianee

AU - Lacouture, Mario

AU - Gahl, William A.

AU - Stephens, Philip J.

AU - Miller, Vincent A.

AU - Ross, Jeffrey S.

AU - Ali, Siraj M.

AU - Briggs, Samuel R.

AU - Fasan, Omotayo

AU - Block, Jared

AU - Heritier, Sebastien

AU - Donadieu, Jean

AU - Solit, David B.

AU - Hyman, David M.

AU - Baselga, Jose

AU - Janku, Filip

AU - Taylor, Barry S.

AU - Park, Christopher Y.

AU - Amoura, Zahir

AU - Dogan, Ahmet

AU - Emile, Jean Francois

AU - Rosen, Neal

AU - Gruber, Tanja A.

AU - Abdel-Wahab, Omar

PY - 2016/2/1

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