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; 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

doi:10.1158/2159-8290.CD-16-0330

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. OndrejkaEric 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

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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.

Original language	English
Pages (from-to)	369-379
Number of pages	11
Journal	Cancer discovery
Volume	7
Issue number	4
DOIs	https://doi.org/10.1158/2159-8290.CD-16-0330
State	Published - Apr 2017

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McKinney, M., Moffitt, A. B., Gaulard, P., Travert, M., Leval, L. D., Raffeld, A. N. M., Jaffe, E. S., Pittaluga, S., Xi, L., Heavican, T., Iqbal, J., Belhadj, K., Delfau-Larue, M. H., Fataccioli, V., Czader, M. B., Lossos, I. S., Chapman-Fredricks, J. R., Richards, K. L., Fedoriw, Y., ... 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

@article{d5c6177064a54d58ad5231b17a34f325,

title = "The genetic basis of hepatosplenic T-cell lymphoma",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",

year = "2017",

month = apr,

doi = "10.1158/2159-8290.CD-16-0330",

language = "English",

volume = "7",

pages = "369--379",

journal = "Cancer discovery",

issn = "2159-8274",

number = "4",

}

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

TY - JOUR

T1 - The genetic basis of hepatosplenic T-cell lymphoma

AU - McKinney, Matthew

AU - Moffitt, Andrea B.

AU - Gaulard, Philippe

AU - Travert, Marion

AU - Leval, Laurence De

AU - Raffeld, Alina Nicolae Mark

AU - Jaffe, Elaine S.

AU - Pittaluga, Stefania

AU - Xi, Liqiang

AU - Heavican, Tayla

AU - Iqbal, Javeed

AU - Belhadj, Karim

AU - Delfau-Larue, Marie Helene

AU - Fataccioli, Virginie

AU - Czader, Magdalena B.

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.

AU - Mehta-Shah, Neha

AU - Horwitz, Steven

AU - Bernal-Mizrachi, Leon

AU - Flowers, Christopher R.

AU - Beaven, Anne W.

AU - Parihar, Mayur

AU - Baseggio, Lucile

AU - Parrens, Marie

AU - Moreau, Anne

AU - Sujobert, Pierre

AU - Pilichowska, Monika

AU - Evens, Andrew M.

AU - Chadburn, Amy

AU - Au-Yeung, Rex K.H.

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

AU - Reddy, Anupama

AU - Love, Cassandra

AU - Levy, Shawn

AU - Zhuang, Yuan

AU - Datta, Jyotishka

AU - Dunson, David B.

AU - Davé, Sandeep S.

PY - 2017/4

Y1 - 2017/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85017152143&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-16-0330

DO - 10.1158/2159-8290.CD-16-0330

M3 - Article

C2 - 28122867

AN - SCOPUS:85017152143

SN - 2159-8274

VL - 7

SP - 369

EP - 379

JO - Cancer discovery

JF - Cancer discovery

IS - 4

ER -

The genetic basis of hepatosplenic T-cell lymphoma

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