Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma

Tayla B. Heavican, Alyssa Bouska, Jiayu Yu, Waseem Lone, Catalina Amador, Qiang Gong, Weiwei Zhang, Yuping Li, Bhavana J. Dave, Maarja Liisa Nairismägi, Timothy C. Greiner, Julie Vose, Dennis D. Weisenburger, Cynthia Lachel, Chao Wang, Kai Fu, Jadd M. Stevens, Soon Thye Lim, Choon Kiat Ong, Randy D. GascoyneEdoardo Missiaglia, Francois Lemonnier, Corinne Haioun, Sylvia Hartmann, Martin Bjerregård Pedersen, Maria Antonella Laginestra, Ryan A. Wilcox, Bin Tean Teh, Noriaki Yoshida, Koichi Ohshima, Masao Seto, Andreas Rosenwald, German Ott, Elias Campo, Lisa M. Rimsza, Elaine S. Jaffe, Rita M. Braziel, Francesco d’Amore, Giorgio Inghirami, Francesco Bertoni, Laurence de Leval, Philippe Gaulard, Louis M. Staudt, Timothy W. McKeithan, Stefano Pileri, Wing C. Chan, Javeed Iqbal

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2R172 mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

Original languageEnglish (US)
Pages (from-to)1664-1676
Number of pages13
JournalBlood
Volume133
Issue number15
DOIs
StatePublished - Apr 11 2019

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Peripheral T-Cell Lymphoma
T-cells
T-Cell Lymphoma
Mutation
Genes
Gene Expression Profiling
Gene expression
Chromosomes, Human, Pair 5
Biological Therapy
Gene Targeting
RNA Stability
DNA Methylation
T-Cell Antigen Receptor
Tumor Suppressor Genes
Phosphatidylinositol 3-Kinases
Proteolysis
Chromosomes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. / Heavican, Tayla B.; Bouska, Alyssa; Yu, Jiayu; Lone, Waseem; Amador, Catalina; Gong, Qiang; Zhang, Weiwei; Li, Yuping; Dave, Bhavana J.; Nairismägi, Maarja Liisa; Greiner, Timothy C.; Vose, Julie; Weisenburger, Dennis D.; Lachel, Cynthia; Wang, Chao; Fu, Kai; Stevens, Jadd M.; Lim, Soon Thye; Ong, Choon Kiat; Gascoyne, Randy D.; Missiaglia, Edoardo; Lemonnier, Francois; Haioun, Corinne; Hartmann, Sylvia; Pedersen, Martin Bjerregård; Laginestra, Maria Antonella; Wilcox, Ryan A.; Teh, Bin Tean; Yoshida, Noriaki; Ohshima, Koichi; Seto, Masao; Rosenwald, Andreas; Ott, German; Campo, Elias; Rimsza, Lisa M.; Jaffe, Elaine S.; Braziel, Rita M.; d’Amore, Francesco; Inghirami, Giorgio; Bertoni, Francesco; de Leval, Laurence; Gaulard, Philippe; Staudt, Louis M.; McKeithan, Timothy W.; Pileri, Stefano; Chan, Wing C.; Iqbal, Javeed.

In: Blood, Vol. 133, No. 15, 11.04.2019, p. 1664-1676.

Research output: Contribution to journalArticle

Heavican, TB, Bouska, A, Yu, J, Lone, W, Amador, C, Gong, Q, Zhang, W, Li, Y, Dave, BJ, Nairismägi, ML, Greiner, TC, Vose, J, Weisenburger, DD, Lachel, C, Wang, C, Fu, K, Stevens, JM, Lim, ST, Ong, CK, Gascoyne, RD, Missiaglia, E, Lemonnier, F, Haioun, C, Hartmann, S, Pedersen, MB, Laginestra, MA, Wilcox, RA, Teh, BT, Yoshida, N, Ohshima, K, Seto, M, Rosenwald, A, Ott, G, Campo, E, Rimsza, LM, Jaffe, ES, Braziel, RM, d’Amore, F, Inghirami, G, Bertoni, F, de Leval, L, Gaulard, P, Staudt, LM, McKeithan, TW, Pileri, S, Chan, WC & Iqbal, J 2019, 'Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma', Blood, vol. 133, no. 15, pp. 1664-1676. https://doi.org/10.1182/blood-2018-09-872549
Heavican, Tayla B. ; Bouska, Alyssa ; Yu, Jiayu ; Lone, Waseem ; Amador, Catalina ; Gong, Qiang ; Zhang, Weiwei ; Li, Yuping ; Dave, Bhavana J. ; Nairismägi, Maarja Liisa ; Greiner, Timothy C. ; Vose, Julie ; Weisenburger, Dennis D. ; Lachel, Cynthia ; Wang, Chao ; Fu, Kai ; Stevens, Jadd M. ; Lim, Soon Thye ; Ong, Choon Kiat ; Gascoyne, Randy D. ; Missiaglia, Edoardo ; Lemonnier, Francois ; Haioun, Corinne ; Hartmann, Sylvia ; Pedersen, Martin Bjerregård ; Laginestra, Maria Antonella ; Wilcox, Ryan A. ; Teh, Bin Tean ; Yoshida, Noriaki ; Ohshima, Koichi ; Seto, Masao ; Rosenwald, Andreas ; Ott, German ; Campo, Elias ; Rimsza, Lisa M. ; Jaffe, Elaine S. ; Braziel, Rita M. ; d’Amore, Francesco ; Inghirami, Giorgio ; Bertoni, Francesco ; de Leval, Laurence ; Gaulard, Philippe ; Staudt, Louis M. ; McKeithan, Timothy W. ; Pileri, Stefano ; Chan, Wing C. ; Iqbal, Javeed. / Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. In: Blood. 2019 ; Vol. 133, No. 15. pp. 1664-1676.
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title = "Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma",
abstract = "Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50{\%} of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2R172 mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.",
author = "Heavican, {Tayla B.} and Alyssa Bouska and Jiayu Yu and Waseem Lone and Catalina Amador and Qiang Gong and Weiwei Zhang and Yuping Li and Dave, {Bhavana J.} and Nairism{\"a}gi, {Maarja Liisa} and Greiner, {Timothy C.} and Julie Vose and Weisenburger, {Dennis D.} and Cynthia Lachel and Chao Wang and Kai Fu and Stevens, {Jadd M.} and Lim, {Soon Thye} and Ong, {Choon Kiat} and Gascoyne, {Randy D.} and Edoardo Missiaglia and Francois Lemonnier and Corinne Haioun and Sylvia Hartmann and Pedersen, {Martin Bjerreg{\aa}rd} and Laginestra, {Maria Antonella} and Wilcox, {Ryan A.} and Teh, {Bin Tean} and Noriaki Yoshida and Koichi Ohshima and Masao Seto and Andreas Rosenwald and German Ott and Elias Campo and Rimsza, {Lisa M.} and Jaffe, {Elaine S.} and Braziel, {Rita M.} and Francesco d’Amore and Giorgio Inghirami and Francesco Bertoni and {de Leval}, Laurence and Philippe Gaulard and Staudt, {Louis M.} and McKeithan, {Timothy W.} and Stefano Pileri and Chan, {Wing C.} and Javeed Iqbal",
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day = "11",
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TY - JOUR

T1 - Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma

AU - Heavican, Tayla B.

AU - Bouska, Alyssa

AU - Yu, Jiayu

AU - Lone, Waseem

AU - Amador, Catalina

AU - Gong, Qiang

AU - Zhang, Weiwei

AU - Li, Yuping

AU - Dave, Bhavana J.

AU - Nairismägi, Maarja Liisa

AU - Greiner, Timothy C.

AU - Vose, Julie

AU - Weisenburger, Dennis D.

AU - Lachel, Cynthia

AU - Wang, Chao

AU - Fu, Kai

AU - Stevens, Jadd M.

AU - Lim, Soon Thye

AU - Ong, Choon Kiat

AU - Gascoyne, Randy D.

AU - Missiaglia, Edoardo

AU - Lemonnier, Francois

AU - Haioun, Corinne

AU - Hartmann, Sylvia

AU - Pedersen, Martin Bjerregård

AU - Laginestra, Maria Antonella

AU - Wilcox, Ryan A.

AU - Teh, Bin Tean

AU - Yoshida, Noriaki

AU - Ohshima, Koichi

AU - Seto, Masao

AU - Rosenwald, Andreas

AU - Ott, German

AU - Campo, Elias

AU - Rimsza, Lisa M.

AU - Jaffe, Elaine S.

AU - Braziel, Rita M.

AU - d’Amore, Francesco

AU - Inghirami, Giorgio

AU - Bertoni, Francesco

AU - de Leval, Laurence

AU - Gaulard, Philippe

AU - Staudt, Louis M.

AU - McKeithan, Timothy W.

AU - Pileri, Stefano

AU - Chan, Wing C.

AU - Iqbal, Javeed

PY - 2019/4/11

Y1 - 2019/4/11

N2 - Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2R172 mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

AB - Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2R172 mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

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