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Blood. 2016 Sep 15;128(11):1490-502. doi: 10.1182/blood-2016-02-698977. Epub 2016 Jul 1.

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.

Author information

1
Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
2
SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland;
3
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada; Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada;
4
INSERM U955, Université Paris-Est, Département de Pathologie, Hôpital Henri-Mondor, Créteil, France;
5
Department of Biochemistry, University of Lausanne, Lausanne, Switzerland;
6
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
7
Service d'Anatomie et cytologie pathologiques, Hôpital Necker, Paris, France;
8
Service d'Anatomie et cytologie pathologiques, Hôpital Saint-Antoine, Paris, France;
9
Service d'Anatomie pathologique, Hôpital Avicenne, Bobigny, France;
10
Hématologie clinique, CHU Liège, Liège, Belgium;
11
SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
12
Service de Biostatistiques, GH Necker-Enfants Malades, Paris, France;
13
Plate-forme de Génomique Fonctionnelle et Structurale, Institut Pour la Recherche sur le Cancer de Lille, Lille, France;
14
INSERM U1170, Institut Gustave Roussy, Villejuif, France;
15
SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland;
16
Hémopathies lymphoides, CHU Henri Mondor, Creteil, France;
17
Hématologie Clinique, CHU Estaing, Clermont-Ferrand, France; and.
18
Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada.

Abstract

Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas.

PMID:
27369867
DOI:
10.1182/blood-2016-02-698977
[Indexed for MEDLINE]
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