Diffuse Large B-Cell Lymphoma (DLBCL)

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and it is characterized by the formation of abnormally large B-cells originating in the lymphatic system. It is an aggressive cancer resulting in rapidly growing masses that may spread to extranodal organs and tissues.¹ 

Diffuse large B-cell lymphoma is not genetically inherited, although a family history of lymphoma is a risk factor. More often, DLBCL results from isolated (de novo) genetic mutations, but it may also progress from less aggressive forms of lymphoma such as follicular lymphoma and chronic lymphocytic leukemia.^1,2

DLBCL Molecular Subtypes

During the process of maturation, B cells undergo a germinal center reaction which exposes them to a foreign antigen. In DLBCL, B cells are malignantly transformed following the germinal center reaction.³ 

Based on B-cell response to this germinal center reaction, DLBCL is categorized into 2 major molecular subtypes: germinal center B-cell (GCB) DLBCL and activated B-cell (ABC) DLBCL. GCB DLBCL B cells form in the dark zone of the germinal center compartment and do not express early post-germinal center differentiation markers. These abnormal GCB B cells experience somatic hypermutation of their immunoglobulin genes. ABC DLBCL B cells contain a transcriptional signature and form either in the light zone of the germinal center or immediately upon exit from the germinal center.^3,4 A third subgroup consists of the unclassified types of DLBCL that cannot be categorized as either GCB or ABC subtypes.⁴

Read more about DLBCL types

Common Genetic Mutations Within DLBCL Molecular Subtypes

Diffuse large B-cell lymphoma is genetically heterogeneous with different pathologic genetic alterations within the 2 major subtypes. In a 2017 study, Reddy and colleagues found that the most common GCB subtype genetic mutations include EZH2, SGK1, GNA13, STAT6, TNFRSF14, and SOCS1 mutations, while the most common ABC subtype genetic mutations include those in the ETV6, PIM1, MYD88, and TBL1XR1 genes.⁵ 

Pasqualucci and Dalla-Favera discovered similar results in a 2018 study, reporting the most common GCB subtype genetic mutations in the BCL2, GNA13, EZH2, TNFRSF14, BCL6 BSE1, MYC, and PTEN genes and the most common ABC subtype mutations in the TNFAIP3, MYD88, CDKN2A, BCL2, PRDM1, CD79A/B, and CARD11 genes. They found that genetic mutations common to both subtypes included those in the BCL6, MLL2/MLL3, CREBBP/EP300, B2M/CD58, TP53, MEF2B, and FOXO1 genes.³

Germinal center B-cell DLBCL correlates with BCL2 gene translocations, while activated B-cell DLBCL correlates with the activation of the antiapoptotic nuclear factor kappa B (NF-κB) signaling pathway (CARD11).⁶

Types of Genetic Mutations in DLBCL

Two mechanisms damage genetic material in DLBCL: chromosomal translocations and aberrant somatic hypermutation. Genetic mutations due to these 2 mechanisms cause dysfunction during the immunoglobulin DNA remodeling processes of B cells. DLBCL-associated chromosomal translocations commonly occur in BCL6, BCL2, and MYC.^3,7 Aberrant somatic hypermutation causes multiple genetic mutations, especially in the PIM1 and MYC proto-oncogenes.³  

More than 150 genetic drivers contribute to the development of DLBCL. Missense mutations or copy number gains affect the function of oncogenes, commonly BCL2, CARD11, and IRF4. Truncating mutations and/or copy number losses affect the function of tumor suppressor genes such as SPEN, CDKN2A, and TNFAIP3.⁵

In 2013, Zhang and colleagues identified 322 DLBCL cancer genes that demonstrated recurrent mutations following whole-genome and -exome sequencing of 73 primary DLBCL tumors. Identification of these genetic alterations provided insights into novel pathways that contribute to the pathogenesis of DLBCL involving chromatic modification (ARID1A and MEF2B), WNT signaling (WIF1), B-cell lineage (GNA13, POU2F2, and IRF8), NF-κB signaling (CARD11 and TNFAIP3), and PI3 kinases (PIK2CD, MTOR, and PIK3R1).⁸  

Patients with DLBCL presenting with lymphomatous effusions frequently demonstrated altered expression of 8 genes (MUC4, SLC35G6, TP53BP2, ARAP3, PDIA4, HDAC1, MDM2, and IL13RA1) and produced 3 proteins (MUC4, MDM2, and HDAC1) commonly associated with the histone deacetylase (HDAC)-related chromatin remodeling pathway and the TP53-MDM2 pathway.⁹ Mutations or deletions in TP53, a tumor suppressor gene, cause uncontrolled cell proliferation and decrease survival rates in patients with DLBCL.⁶

Overall, various aspects of genetic mutations and chromosomal translocations, such as epigenetic modifications, immune escape, uncontrolled cell proliferation, inhibition of apoptosis, BCL6 expression deregulation, problems with repairing damaged DNA, changes to the cell cycle, and other functional alterations contribute to the development of DLBCL.³

Multiple Mutations in Diffuse Large B-Cell Lymphoma

Double-hit lymphoma arises when chromosomal translocations occur in both MYC and either BCL2 or BCL6.⁵ Triple-hit lymphoma refers to chromosomal translocations in MYC, BCL2, and BCL6.¹¹ Double-expressor DLBCL indicates the high co-expression of MYC and BCL2, which typically results in poorer outcomes.⁵

Read more about DLBCL prognosis

Genetic Subtypes in DLBCL

In 2018, Schmitz and colleagues discovered 4 genetic subtypes (N1, BN2, MCD, and EZB) in DLBCL after analyzing 574 DLBCL biopsy samples. NOTCH1 mutations led to the N1 subtype. A combination of BCL6 fusions and NOTCH2 mutations resulted in the BN2 subtype. The co-occurrence of mutations in MYD88 and CD79B led to the MCD subtype. A combination of EZH2 mutations and BCL2 translocations resulted in the EZB subtype.¹⁰ Other studies have also reported the co-occurrence of mutations in MYD88 and CD79B within the MCD subtype.⁷

Disruption of B-cell differentiation characterizes the N1 subtype. Dysregulation of the NOTCH and NF-κB pathways characterize the BN2 subtype. Immune escape characterizes the MCD subtype. Problems with epigenetic regulation occur in the EZB subtype.⁴ 

References

1. Freedman AS, Friedberg JW. Patient education: diffuse large B cell lymphoma in adults (beyond the basics). UpToDate, Inc. Updated July 22, 2022. Accessed August 12, 2022.
2. Bakhshi TJ, Georgel PT. Genetic and epigenetic determinants of diffuse large B-cell lymphoma. Blood Cancer J. 2020;10(12):123. doi:10.1038/s41408-020-00389-w
3. Pasqualucci L, Dalla-Favera R. Genetics of diffuse large B-cell lymphoma. Blood. 2018;131(21):2307-2319. doi:10.1182/blood-2017-11-764332
4. Miao Y, Medeiros LJ, Li J, Young KH. Diffuse large B-cell lymphoma with molecular variations more than ABC and GCB classification. Precis Cancer Med. 2018;1:4. doi:10.21037/pcm.2018.06.03
5. Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171(2):481-494.e15. doi:10.1016/j.cell.2017.09.027
6. Gandhi S. Diffuse large B-cell lymphoma (DLBCL): pathophysiology. Medscape. Updated May 6, 2021. Accessed August 12, 2022.
7. Zhang W, Yang L, Guan YQ, et al. Novel bioinformatic classification system for genetic signatures identification in diffuse large B-cell lymphoma. BMC Cancer. 2020;20(1):714. doi:10.1186/s12885-020-07198-1
8. Zhang J, Grubor V, Love CL, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110(4):1398-1403. doi:10.1073/pnas.1205299110
9. Abdollahi S, Dehghanian SZ, Hung LY, et al. Deciphering genes associated with diffuse large B-cell lymphoma with lymphomatous effusions: a mutational accumulation scoring approach. Biomark Res. 2021;9(1):74. doi:10.1186/s40364-021-00330-8
10. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396-1407. doi:10.1056/NEJMoa1801445
11. Huang W, Medeiros LJ, Lin P, et al. MYC/BCL2/BCL6 triple hit lymphoma: a study of 40 patients with a comparison to MYC/BCL2 and MYC/BCL6 double hit lymphomas. Mod Pathol. 2018;31(9):1470-1478. doi:10.1038/s41379-018-0067-x

Reviewed by Harshi Dhingra, MD, on 8/13/2022.

---

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.