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Non-Hodgkin Lymphoma
Genetic evolution of in situ follicular neoplasia to aggressive B-cell lymphoma of germinal center subtype
Antonio Vogelsberg,1 Julia Steinhilber,1 Barbara Mankel,1 Birgit Federmann,1 Janine Schmidt,1 Ivonne A. Montes-Mojarro,1 Katrin Hüttl,2 Maria Rodriguez- Pinilla,3 Praveen Baskaran,4 Sven Nahnsen,4 Miguel A. Piris,3 German Ott,2 Leticia Quintanilla-Martinez,1 Irina Bonzheim,1# and Falko Fend1#
1Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany; 2Department of Clinical Pathology, Robert- Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; 3Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain and 4Quantitative Biology Center, University of Tübingen, Tübingen, Germany
#IB and FF contributed equally as co-senior authors.
ABSTRACT
In situ follicular neoplasia (ISFN) is the earliest morphologically iden- tifiable precursor of follicular lymphoma (FL). Although it is geneti- cally less complex than FL and has low risk for progression, ISFN already harbors secondary genetic alterations, in addition to the defin- ing t(14;18)(q32;q21) translocation. FL, in turn, frequently progresses to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). By BCL2 staining of available reactive lymphoid tissue obtained at any time point in patients with aggressive B-cell lymphoma (BCL), we identified ten paired cases of ISFN and DLBCL/HGBL, includ- ing six de novo tumors and four tumors transformed from FL as an inter- mediate step, and investigated their clonal evolution using microdissec- tion and next-generation sequencing. A clonal relationship between ISFN and aggressive BCL was established by immunoglobulin and/or BCL2 rearrangements and/or the demonstration of shared somatic mutations for all ten cases. Targeted sequencing revealed CREBBP, KMT2D, EZH2, TNFRSF14 and BCL2 as the genes most frequently mutated already in ISFN. Based on the distribution of private and shared mutations, two patterns of clonal evolution were evident. In most cases, the aggressive lymphoma, ISFN and, when present, FL revealed diver- gent evolution from a common progenitor, whereas linear evolution with sequential accumulation of mutations was less frequent. In conclu- sion, we demonstrate for the first time that t(14;18)+ aggressive BCL can arise from ISFN without clinically evident FL as an intermediate step and that during this progression, branched evolution is common.
Introduction
B-cell lymphomas (BCL) are thought to arise from premalignant precursor cells by stepwise accumulation of mutations fostering survival and clonal expansion. Whereas some premalignant lesions such as monoclonal gammopathy of unknown significance (MGUS) and monoclonal B-cell lymphocytosis (MBL) have been known for many years, there are no known precursors for de novo aggressive BCL. Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) is the most frequent form of BCL and represents 25-35% of adult BCL in the Western world. Based on gene expression profiling DLBCL can be sub-classified into activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes.1,2 Approximately 20-30% of DLBCL, mostly of GCB subtype, exhibit the t(14;18)(q32;q21) translocation, the hallmark of follicular lymphoma (FL).3 This translocation causes constitutive overexpression of the anti-apoptotic protein
Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2673-2681
Correspondence:
FALKO FEND
falko.fend@med.uni-tuebingen.de
IRINA BONZHEIM
irina.bonzheim@med.uni-tuebingen.de
Received: April 8, 2020. Accepted: August 12, 2020. Pre-published: August 27, 2020.
https://doi.org/10.3324/haematol.2020.254854 ©2021 Ferrata Storti Foundation
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