The genetic basis of hepatosplenic T-cell lymphoma

Matthew McKinney, Andrea B. Moffitt, Philippe Gaulard, Marion Travert, Laurence De Leval, Alina Nicolae Mark Raffeld, Elaine S. Jaffe, Stefania Pittaluga, Liqiang Xi, Tayla Heavican, Javeed Iqbal, Karim Belhadj, Marie Helene Delfau-Larue, Virginie Fataccioli, Magdalena B. Czader, Izidore S. Lossos, Jennifer R. Chapman-Fredricks, Kristy L. Richards, Yuri Fedoriw, Sarah L. Ondrejka & 35 others Eric D. Hsi, Lawrence Low, Dennis Weisenburger, Wing C. Chan, Neha Mehta-Shah, Steven Horwitz, Leon Bernal-Mizrachi, Christopher R. Flowers, Anne W. Beaven, Mayur Parihar, Lucile Baseggio, Marie Parrens, Anne Moreau, Pierre Sujobert, Monika Pilichowska, Andrew M. Evens, Amy Chadburn, Rex K.H. Au-Yeung, Gopesh Srivastava, William W.L. Choi, John R. Goodlad, Igor Aurer, Sandra Basic-Kinda, Randy D. Gascoyne, Nicholas S. Davis, Guojie Li, Jenny Zhang, Deepthi Rajagopalan, Anupama Reddy, Cassandra Love, Shawn Levy, Yuan Zhuang, Jyotishka Datta, David B. Dunson, Sandeep S. Davé

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. SIGNIFICANCE: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease.

Original languageEnglish (US)
Pages (from-to)369-379
Number of pages11
JournalCancer Discovery
Volume7
Issue number4
DOIs
StatePublished - Apr 1 2017

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T-Cell Lymphoma
Exome
Tumor Suppressor Genes
Mutation
Genes
Inborn Genetic Diseases
Critical Pathways
Gene Dosage
Rare Diseases
Chromatin
Lymphoma
Cell Survival

ASJC Scopus subject areas

  • Oncology

Cite this

McKinney, M., Moffitt, A. B., Gaulard, P., Travert, M., Leval, L. D., Raffeld, A. N. M., ... Davé, S. S. (2017). The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discovery, 7(4), 369-379. https://doi.org/10.1158/2159-8290.CD-16-0330

The genetic basis of hepatosplenic T-cell lymphoma. / McKinney, Matthew; Moffitt, Andrea B.; Gaulard, Philippe; Travert, Marion; Leval, Laurence De; Raffeld, Alina Nicolae Mark; Jaffe, Elaine S.; Pittaluga, Stefania; Xi, Liqiang; Heavican, Tayla; Iqbal, Javeed; Belhadj, Karim; Delfau-Larue, Marie Helene; Fataccioli, Virginie; Czader, Magdalena B.; Lossos, Izidore S.; Chapman-Fredricks, Jennifer R.; Richards, Kristy L.; Fedoriw, Yuri; Ondrejka, Sarah L.; Hsi, Eric D.; Low, Lawrence; Weisenburger, Dennis; Chan, Wing C.; Mehta-Shah, Neha; Horwitz, Steven; Bernal-Mizrachi, Leon; Flowers, Christopher R.; Beaven, Anne W.; Parihar, Mayur; Baseggio, Lucile; Parrens, Marie; Moreau, Anne; Sujobert, Pierre; Pilichowska, Monika; Evens, Andrew M.; Chadburn, Amy; Au-Yeung, Rex K.H.; Srivastava, Gopesh; Choi, William W.L.; Goodlad, John R.; Aurer, Igor; Basic-Kinda, Sandra; Gascoyne, Randy D.; Davis, Nicholas S.; Li, Guojie; Zhang, Jenny; Rajagopalan, Deepthi; Reddy, Anupama; Love, Cassandra; Levy, Shawn; Zhuang, Yuan; Datta, Jyotishka; Dunson, David B.; Davé, Sandeep S.

In: Cancer Discovery, Vol. 7, No. 4, 01.04.2017, p. 369-379.

Research output: Contribution to journalArticle

McKinney, M, Moffitt, AB, Gaulard, P, Travert, M, Leval, LD, Raffeld, ANM, Jaffe, ES, Pittaluga, S, Xi, L, Heavican, T, Iqbal, J, Belhadj, K, Delfau-Larue, MH, Fataccioli, V, Czader, MB, Lossos, IS, Chapman-Fredricks, JR, Richards, KL, Fedoriw, Y, Ondrejka, SL, Hsi, ED, Low, L, Weisenburger, D, Chan, WC, Mehta-Shah, N, Horwitz, S, Bernal-Mizrachi, L, Flowers, CR, Beaven, AW, Parihar, M, Baseggio, L, Parrens, M, Moreau, A, Sujobert, P, Pilichowska, M, Evens, AM, Chadburn, A, Au-Yeung, RKH, Srivastava, G, Choi, WWL, Goodlad, JR, Aurer, I, Basic-Kinda, S, Gascoyne, RD, Davis, NS, Li, G, Zhang, J, Rajagopalan, D, Reddy, A, Love, C, Levy, S, Zhuang, Y, Datta, J, Dunson, DB & Davé, SS 2017, 'The genetic basis of hepatosplenic T-cell lymphoma', Cancer Discovery, vol. 7, no. 4, pp. 369-379. https://doi.org/10.1158/2159-8290.CD-16-0330
McKinney M, Moffitt AB, Gaulard P, Travert M, Leval LD, Raffeld ANM et al. The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discovery. 2017 Apr 1;7(4):369-379. https://doi.org/10.1158/2159-8290.CD-16-0330
McKinney, Matthew ; Moffitt, Andrea B. ; Gaulard, Philippe ; Travert, Marion ; Leval, Laurence De ; Raffeld, Alina Nicolae Mark ; Jaffe, Elaine S. ; Pittaluga, Stefania ; Xi, Liqiang ; Heavican, Tayla ; Iqbal, Javeed ; Belhadj, Karim ; Delfau-Larue, Marie Helene ; Fataccioli, Virginie ; Czader, Magdalena B. ; Lossos, Izidore S. ; Chapman-Fredricks, Jennifer R. ; Richards, Kristy L. ; Fedoriw, Yuri ; Ondrejka, Sarah L. ; Hsi, Eric D. ; Low, Lawrence ; Weisenburger, Dennis ; Chan, Wing C. ; Mehta-Shah, Neha ; Horwitz, Steven ; Bernal-Mizrachi, Leon ; Flowers, Christopher R. ; Beaven, Anne W. ; Parihar, Mayur ; Baseggio, Lucile ; Parrens, Marie ; Moreau, Anne ; Sujobert, Pierre ; Pilichowska, Monika ; Evens, Andrew M. ; Chadburn, Amy ; Au-Yeung, Rex K.H. ; Srivastava, Gopesh ; Choi, William W.L. ; Goodlad, John R. ; Aurer, Igor ; Basic-Kinda, Sandra ; Gascoyne, Randy D. ; Davis, Nicholas S. ; Li, Guojie ; Zhang, Jenny ; Rajagopalan, Deepthi ; Reddy, Anupama ; Love, Cassandra ; Levy, Shawn ; Zhuang, Yuan ; Datta, Jyotishka ; Dunson, David B. ; Davé, Sandeep S. / The genetic basis of hepatosplenic T-cell lymphoma. In: Cancer Discovery. 2017 ; Vol. 7, No. 4. pp. 369-379.
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abstract = "Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62{\%} of cases. HSTLs manifest frequent mutations in STAT5B (31{\%}), STAT3 (9{\%}), and PIK3CD (9{\%}), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. SIGNIFICANCE: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease.",
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AU - Raffeld, Alina Nicolae Mark

AU - Jaffe, Elaine S.

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AU - Lossos, Izidore S.

AU - Chapman-Fredricks, Jennifer R.

AU - Richards, Kristy L.

AU - Fedoriw, Yuri

AU - Ondrejka, Sarah L.

AU - Hsi, Eric D.

AU - Low, Lawrence

AU - Weisenburger, Dennis

AU - Chan, Wing C.

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AU - Srivastava, Gopesh

AU - Choi, William W.L.

AU - Goodlad, John R.

AU - Aurer, Igor

AU - Basic-Kinda, Sandra

AU - Gascoyne, Randy D.

AU - Davis, Nicholas S.

AU - Li, Guojie

AU - Zhang, Jenny

AU - Rajagopalan, Deepthi

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