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,
Christian Kohler,
Raphael Witzig,
Markus Kreuz,
Ellen Leich,
Wolfram Klapper,
Michael Hummel,
Markus Loeffler,
Lorenz Trümper,
Rainer Spang,
Andreas Rosenwald,
German Ott,
for the Molecular Mechanisms in Malignant Lymphomas (MMML) Network Project
Affiliations
Heike Horn
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Germany
Christian Kohler
Statistical Bioinformatics Department, Institute of Functional Genomics, University of Regensburg, Germany
Raphael Witzig
Department of Clinical Pathology, Robert Bosch Krankenhaus, Stuttgart, Germany
Markus Kreuz
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany
Ellen Leich
Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany
Wolfram Klapper
Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
Michael Hummel
Institute of Pathology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Germany
Markus Loeffler
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany
Lorenz Trümper
Department of Hematology and Oncology, Georg-August University of Göttingen, Germany
Rainer Spang
Statistical Bioinformatics Department, Institute of Functional Genomics, University of Regensburg, Germany
Andreas Rosenwald
Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany
German Ott
Department of Clinical Pathology, Robert Bosch Krankenhaus, Stuttgart, Germany
for the Molecular Mechanisms in Malignant Lymphomas (MMML) Network Project
A linear 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 differences 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 pattern, 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 genetic profiles of the different histological FL subtypes that point to a closer relationship between FL1/2 and FL3A, and separates them from FL3B.
