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J Mol Diagn. 2015 Apr 9. pii: S1525-1578(15)00046-X. doi: 10.1016/j.jmoldx.2015.01.007. [Epub ahead of print]

Accurate Classification of Germinal Center B-Cell-Like/Activated B-Cell-Like Diffuse Large B-Cell Lymphoma Using a Simple and Rapid Reverse Transcriptase-Multiplex Ligation-Dependent Probe Amplification Assay: A CALYM Study.

Author information

1
INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
2
INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France. Electronic address: philippe.ruminy@chb.unicancer.fr.
3
Department of Clinical Hematology, Prof. Dr. Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania.
4
INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France; Department of Pathology, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
5
INSERM UMRS 872, APHP Necker Hospital, Université Paris Descartes, Paris, France.
6
Functional Genomic Platform, UDSL, IFR114, IRCL, Lille, France.
7
Department of Pathology, APHP Necker Hospital, Université Paris Descartes, Paris, France.
8
INSERM U917, Laboratoire d'Hématologie, CHU Pontchaillou, Rennes, France.
9
CNRS UMR 5239, ENS, HCL, Faculté de Médecine Lyon Sud, Université Claude Bernard, Lyon, France.
10
Unité Hémopathies Lymphoïdes, Equipe 09, APHP Hopital Henri Mondor, Université Paris Est, Créteil, France.
11
INSERM U955, Equipe 09, APHP Hopital Henri Mondor, Université Paris Est, Créteil, France.

Abstract

Diffuse large B-cell lymphoma, the most common non-Hodgkin lymphoma, is subdivided into germinal center B-cell-like and activated B-cell-like subtypes. Unfortunately, these lymphomas are difficult to differentiate in routine diagnosis, impeding the development of treatments. Patients with these lymphomas can benefit from specific therapies. We therefore developed a simple and rapid classifier based on a reverse transcriptase multiplex ligation-dependent probe amplification assay and 14 gene signatures. Compared with the Affymetrix U133+2 gold standard, all 46 samples (95% CI, 92%-100%) of a validation cohort classified by both techniques were attributed to the expected subtype. Similarly, 93% of the 55 samples (95% CI, 82%-98%) of a second independent series characterized with a mid-throughput gene expression profiling method were classified correctly. Unclassifiable sample proportions reached 13.2% and 13.8% in these cohorts, comparable with the frequency originally reported. The developed assay was also sensitive enough to obtain reliable results from formalin-fixed, paraffin-embedded samples and flexible enough to include prognostic factors such as MYC/BCL2 co-expression. Finally, in a series of 135 patients, both overall (P = 0.01) and progression-free (P = 0.004) survival differences between the two subtypes were confirmed. Because the multiplex ligation-dependent probe amplification method is already in use and requires only common instruments and reagents, it could easily be applied to clinical trial patient stratification to help in treatment decisions.

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