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Clin Cancer Res. 2016 Jun 15;22(12):2919-28. doi: 10.1158/1078-0432.CCR-15-2305. Epub 2016 Jan 27.

Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study.

Author information

1
Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
2
Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France. LITIS EA 4108, Normandie Université, Rouen, France.
3
Inserm UMRS 872, AP-HP Hôpital Necker, Paris, France.
4
Université de Lille 2, Lille, France.
5
Pathology, AP-HP, Hôpital Necker, Université Paris Descartes, Paris, France.
6
Inserm U917, CHU Pontchaillou, Rennes, France.
7
Unité Hémopathies Lymphoïdes, AP-HP Hôpital Henri Mondor, Créteil, France.
8
IMRB-Inserm U955, AP-HP Hôpital Henri Mondor, Créteil, France.
9
Inserm U728, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Department of Pathology, AP-HP Hôpital Saint-Louis, Paris, France.
10
Department of Pathology, Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada.
11
Laboratoire de Pathologie, AP-HP Hôpital Necker, Paris, France.
12
Laboratoire de Pathologie, AP-HP Hôpital Saint Antoine, Paris, France.
13
CNRS UMR5239, Hospices Civils de Lyon, Lyon, France.
14
Department of Hematology, AP-HP Hôpital Necker, Paris, France.
15
Department of Hematology, Lacassagne Center, Nice, France.
16
CHU Dinant Godinne, UcL Namur, Yvoir, Belgium.
17
Department of Oncology, Lausanne Hospital, Lausanne, Switzerland.
18
Inserm U955 Team 09, AP-HP Hôpital Henri Mondor, Créteil, France.
19
Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France. fabrice.jardin@chb.unicancer.fr.

Abstract

PURPOSE:

Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials.

EXPERIMENTAL DESIGN:

A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20(+)de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays.

RESULTS:

The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell-like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK-STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses.

CONCLUSIONS:

This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919-28. ©2016 AACRSee related commentary by Lim and Elenitoba-Johnson, p. 2829.

PMID:
26819451
DOI:
10.1158/1078-0432.CCR-15-2305
[Indexed for MEDLINE]
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