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Non-Hodgkin Lymphoma
Gene expression profiling reveals a close relationship between follicular lymphoma grade 3A and 3B, but distinct profiles of follicular lymphoma grade 1 and 2
Heike Horn,1 Christian Kohler,2 Raphael Witzig,3 Markus Kreuz,4 Ellen Leich,5 Wolfram Klapper,6 Michael Hummel,7 Markus Loeffler,4 Lorenz Trümper,8 Rainer Spang,2 Andreas Rosenwald5 and German Ott;3 for the Molecular Mechanisms in Malignant Lymphomas (MMML) Network Project
1Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen; 2Statistical Bioinformatics Department, Institute of Functional Genomics, University of Regensburg; 3Department of Clinical Pathology, Robert Bosch Krankenhaus, Stuttgart; 4Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig; 5Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg; 6Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel; 7Institute of Pathology, Campus Benjamin Franklin, Charité– Universitätsmedizin Berlin and 8Department of Hematology and Oncology, Georg-August University of Göttingen, Germany
ABSTRACT
Alinear progression model of follicular lymphomas (FL) FL1, FL2 and FL3A has been favored, since FL3A often co-exist with an FL1/2 component. FL3B, in contrast, is thought to be more closely related to diffuse large B-cell lymphoma (DLBCL), and both are often simultaneously present in one tumor (DLBCL/FL3B). To obtain more detailed insights into follicular lymphoma progression, a comprehensive analysis of a well-defined set of FL1/2 (n=22), FL3A (n=16), FL3B (n=6), DLBCL/FL3B (n=9), and germinal center B-cell-type diffuse large B-cell lymphoma (n=45) was undertaken using gene expression profiling, immunohistochemical stainings and genetic analyses by fluorescence in situ hybridization. While immunohistochemical (CD10, IRF4/MUM1, Ki67, BCL2, BCL6) and genetic profiles (translocations of BCL2, BCL6 and MYC) delineate FL1-3A from FL3B and DLBCL/FL3B, significant dif- ferences were observed between FL1/2 and FL3A upon gene expression profiling. Interestingly, FL3B turned out to be closely related to FL3A, not categorizing within a separate gene expression cluster, and both FL3A and FL3B showed overlapping profiles in between FL1/2 and diffuse large B-cell lymphoma. Finally, based upon their gene expression pat- tern, DLBCL/FL3B represent a composite form of FL3B and DLBCL, with the majority of samples more closely resembling the latter. The fact that gene expression profiling clearly separated FL1/2 from both FL3A and FL3B suggests a closer biological relationship between the latter. This notion, however, is in contrast to immunohistochemical and genet- ic profiles of the different histological FL subtypes that point to a closer relationship between FL1/2 and FL3A, and separates them from FL3B.
Introduction
Follicular lymphoma (FL) comprises approximately 30% of B-cell non-Hodgkin lymphomas (B-NHL) and represents the most common type of indolent B-NHL. FL originates from germinal center B cells (GCB) characterized by expression of CD10 and BCL6. FL consists of a mixture of centroblasts and centrocytes, the rel- ative ratio of which determines the histological grade. While FL1/2 and FL3A con- sist of centrocytes and centroblasts (the difference between them being the num-
Haematologica 2018 Volume 103(7):1182-1190
*HH and CK contributed equally to this work. A full list of MMML members is provided in the Online Supplementary Appendix.
Correspondence:
german.ott@rbk.de
Received: October 24, 2017. Accepted: March 15, 2018. Pre-published: March 22, 2018.
doi:10.3324/haematol.2017.181024
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/7/1182
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