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Both lymphomas are shaped by a recurring set of genetic changes: the t(14;18) translocation that switches on BCL2, mutations in chromatin regulators such as KMT2D, CREBBP and EZH2, and changes in genes such as TNFRSF14, BCL6 and MYC. These papers define those drivers and the genetic subtypes they create.
Not medical advice. These are short, plain-English summaries of published research, written for education. They are not treatment recommendations. Questions about an individual situation belong with a hematologist or oncologist.
Chapuy B, Wood T, et al. Blood. 2025.
The authors validated their five-cluster (C1 to C5) genetic taxonomy of DLBCL in 699 tumors and trained a neural network classifier, DLBclass, to assign individual cases. It reached about 89 to 91% accuracy overall and 97 to 98% for high-confidence assignments, supporting its use in genetically guided clinical trials.
Dreval K, Hilton LK, et al. Blood. 2023.
Whole-genome sequencing of 423 patients compared untransformed FL, transformed FL and de novo DLBCL, revealing two FL subgroups called DLBCL-like FL and constrained FL. Constrained FL, which can be identified from genetic features present at diagnosis, was associated with a lower rate of histologic transformation in validation cohorts.
Mondello P, Tadros S, et al. Cancer Discov. 2020.
The study showed that two classes of CREBBP mutations disrupt the lymphoma epigenome to different degrees and that the affected genes are targets of the BCL6 and HDAC3 repressor complex. Selective HDAC3 inhibitors reversed these changes in laboratory and mouse models, slowing lymphoma growth and restoring immune recognition of tumor cells.
Wright GW, Huang DW, et al. Cancer Cell. 2020.
This paper describes LymphGen, an algorithm that estimates the probability that a DLBCL belongs to each of seven genetic subtypes. The subtypes showed genetic links to other lymphoma types, distinct immune microenvironments and different outcomes after immunochemotherapy.
Rosenwald A, Bens S, et al. J Clin Oncol. 2019.
In 2,383 DLBCL patients treated with R-CHOP or similar therapy, MYC rearrangement appeared in 11% and was linked to shorter survival, mostly within the first two years. The poor outcome was concentrated in double-hit or triple-hit disease, where MYC is joined to an immunoglobulin partner alongside BCL2 and/or BCL6 rearrangements.
Chapuy B, Stewart C, et al. Nat Med. 2018.
A comprehensive genetic analysis of 304 DLBCLs combined mutations, copy-number changes and structural variants to identify five robust subsets, C1 to C5. These included two distinct groups of germinal center B-cell type DLBCL and a group defined by TP53 loss and genomic instability, with signatures that predicted outcome independently of the clinical International Prognostic Index.
Schmitz R, Wright GW, et al. N Engl J Med. 2018.
Using exome, transcriptome and copy-number data from 574 DLBCL biopsies, the study defined four genetic subtypes: MCD, BN2, N1 and EZB, the last marked by EZH2 mutations and BCL2 translocations. The subtypes differed in gene expression and in outcome after immunochemotherapy, laying the groundwork for genetics-based classification.
Boice M, Salloum D, et al. Cell. 2016.
Loss of HVEM (TNFRSF14), one of the most frequently mutated genes in germinal center lymphomas, drove B-cell proliferation and a tumor-supportive microenvironment in mice by breaking HVEM and BTLA signaling. Restoring soluble HVEM, delivered locally by engineered CAR T cells, suppressed lymphoma growth in models.
Zhang J, Dominguez-Sola D, et al. Nat Med. 2015.
FL- and DLBCL-associated KMT2D mutations reduce the enzyme's activity and lower H3K4 methylation in germinal center B cells. In mice, early loss of Kmt2d expanded germinal center B cells and, together with Bcl2 overexpression, increased lymphoma incidence, supporting KMT2D as a tumor suppressor lost early in lymphoma development.
Green MR, Kihira S, et al. Proc Natl Acad Sci U S A. 2015.
By tracing mutations across 59 sequential biopsies from 22 patients, the study found that CREBBP mutations are among the earliest events in follicular lymphoma evolution. CREBBP-mutant tumor cells showed reduced MHC class II antigen presentation, which was linked to fewer and less active tumor-infiltrating T cells.
Correia C, Schneider PA, et al. Blood. 2015.
FL begins with the t(14;18) translocation that switches on BCL2, and this study found additional BCL2 coding mutations in 12% of FL at diagnosis and 53% at transformation. Patients whose tumors carried these mutations at diagnosis had about a 3.6 times higher risk of transformation and shorter lymphoma-specific survival, and some mutant proteins blocked cell death more strongly.
Béguelin W, Popovic R, et al. Cancer Cell. 2013.
EZH2 is required to form germinal centers, where it temporarily silences checkpoint and differentiation genes. Lymphoma-associated EZH2 mutations strengthen this silencing and, together with BCL2, accelerate lymphoma in mice; germinal center B-cell type DLBCLs depended on EZH2, while activated B-cell type DLBCLs did not.
Study the drivers card by card. The follicular lymphoma driver deck has a card for each gene and concept on this page, from BCL2 and the chromatin regulators to immune evasion.
See the driver deck12 papers, newest first. Titles, authors, journals, years and DOIs were checked against PubMed on 2026-10-20. Back to the Research library.