HAEM5:EBV-positive diffuse large B-cell lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

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WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Mature B-cell neoplasms
Type	Large B-cell lymphomas
Subtype(s)	EBV-positive diffuse large B-cell lymphoma

Related Terminology

Acceptable	EBV-positive diffuse large B-cell lymphoma NOS
Not Recommended	EBV-positive diffuse large B-cell lymphoma of the elderly; senile EBV-associated B-cell lymphoproliferative disorder; age-related EBV-positive lymphoproliferative disorder

Gene Rearrangements

Detection of clonal IGH and IGK gene rearrangements supports a neoplastic process and helps differentiate EBV-positive DLBCL from reactive, polyclonal B-cell proliferations. However, the major oncogenic driver rearrangements seen in other aggressive B-cell lymphoma such as the ‘double/triple-hit’ rearrangements involving MYC, BCL2, or BCL6 are rare in EBV-positive DLBCL. Its pathogenesis is driven more by EBV-related mechanisms and distinct genetic alterations than by these characteristic translocations. IRF4 rearrangements involving known partners such as IGH and more recently RHOH have also been described in EBV-positive DLBCL. RHOH, is an RHO GTPase family member and negative regulator of cell growth, has been described as a fusion partner in other lymphoid neoplasms but is more commonly linked to non-coding somatic hypermutation in DLBCL Clinically, morphologically as well as at the molecular level, EBV+DLBCL-IRF4-R resemble and behave like EBV+DLBCL

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes

Individual Region Genomic Gain/Loss/LOH

None reported so far.

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes

Characteristic Chromosomal or Other Global Mutational Patterns

According to the most recent literature, EBV-positive DLBCL shows frequent structural genomic alterations, including recurrent 6q deletions (44%), often involving important tumor-suppressor genes such as PRDM1 and A20, which play key roles in B-cell lymphoma development, although these cases show fewer ANKRD111 and NOTCH2 mutations, suggesting a distinct pathogenic mechanism. Multiple focal amplifications have been reported, most notably 6p25.3 containing IRF4 (35%) and 9p24.1 including PD-L1/PD-L2 and JAK2 (20%), with PD-L1 amplification strongly correlating with protein overexpression. Additional immune-escape and oncogenic amplifications include 1q24.3 (FASL) (22%), 11q24.3 (ETS1/FLI1) (20%), and 2q31.3 containing the lncRNA SChLAP1. Deletions are less common but include broad losses of 18p/18q and a recurrent focal deletion at 11p15.3 impacting the tumor-suppressor DKK3. These structural alterations did not correspond to distinct gene-expression profiles.

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
6q deletions	Tumor-suppressor genes: PRDM1 and A20	Common	D	No	6q deletions can simultaneously affect PRDM1 and TNFAIP3, leading to impaired plasma cell differentiation and dysregulated NF-κB signaling, both of which are critical for normal B-cell function and are implicated in the development and progression of B-cell lymphomas, a well-documented abnormality in EBV-negative ABC-type DLBCL
6p25.3 amplifications	5 different genes including the oncogene IRF4 are located	Common	May be D	No
9p24.1 amplifications	PD-L1/PD-L2 and JAK2	Recurrent	May be T	No	PD-L1 expression in DLBCL is associated with poorer prognosis and may suggest a role for immunotherapy, but it is not yet a standardized factor in guiding routine first-line treatment, as its clinical significance remains evolving and context-dependent

Gene Mutations (SNV/INDEL)

The mutation landscape is primarily characterized by frequent alterations in the NF-κB, WNT, and IL-6/JAK/STAT pathways, distinguishing it from the mutation profile seen in EBV-negative DLBCL-NOS.

According to the most recent literature, frequent mutations in ARID1A, KMT2A, ANKRD11, NOTCH2, and KMT2D (30-45% of cases) are observed in EBV-positive DLBCL, with higher frequencies compared to EBV-negative DLBCL. Additionally, CCR6, CCR7, DAPK1, TNFRSF21, and YY1 were identified as recurrent and specific mutations in EBV-positive DLBCL, differentiating it from other DLBCL subtypes.

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
SOCS1	Loss of function aberration in the SH2 domain	Tumor Suppressor gene	Common	P, T	EXAMPLE: Yes (NCCN)	SOCS1 mutations, especially affecting SOCS-BOX domain, improve prognosis with better PFS and OS, likely due to their role in modulating the JAK-STAT pathway.
STAT3	Activating missense mutations	Oncogene/ Tumor suppressor gene	Common	T		STAT3 is an effective molecular target for ABC-like DLBCL therapy
KMT2D	Inactivating mutations	Tumor Suppressor Gene	Common	D	No	Several tumor suppressor genes such as TNFAIP3 and SOCS3 also become silenced upon KMT2D loss of function. Targeting KDM5 demethylases counteracts KMT2D loss of function in DLBCL, which can open the opportunity for novel combination targeted therapies.
CCR6				D	No	Mutations in CCR6 may act as oncogenic drivers—especially in MALT lymphoma—by disrupting β-arrestin–mediated receptor desensitization, leading to unchecked intracellular signaling.
CCR7				D	No	CCR7 upregulation in EBV-infected cells may promote lymphoid homing and viral persistence, and recurrent CCR7 mutations in EBV+ DLBCL could similarly enhance proliferation and migration, as seen in other cancers.
DAPK1				D, P	No	Oncogenic DAPK1 mutations appear to be unique/ exclusive to EBV+ DLBCL. Prior studies have shown poor prognosis associated with hypermethylation - loss of function mutations in DAPK1 and may similarly contribute to adverse prognosis.
TNFRSF21				D	No	Impaired TNFRSF21/DR6 function has been associated with increased cell proliferation and reduced apoptosis in B- and T-cell malignancies, including EBV-associated AITL
CSNK2B				D	No	CSNK2B, another alteration uniquely seen in EBV⁺ DLBCL, remains poorly characterized and its oncogenic role is not yet well understood.
YY1				D	No	YY1 is a known oncogenic driver in DLBCL, where its overexpression promotes B-cell transformation and tumor progression, independent of EBV status.

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

None identified so far.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
SOCS1; Inactivating mutations	JAK-STAT and interferon gamma (INFγ) signaling pathways	Activation of the JAK-STAT INFγ signaling pathways
STAT3 and STAT6; Activating mutations	Normal cellular events: Survival, proliferation, and differentiation	Tumor cell survival, proliferation, and invasion
TNFAIP3 (A20) and MAP3K14 (NIK); Inactivating mutations	Negative regulation of NF-κB pathway	Abnormal and prolonged activation of the NF-κB pathway
KMT2D and KMT2C; Loss of function mutations	Histone methyltransferases involved in epigenetic regulation; mediate H3K4 mono and demethylation (H4K3me1/2) primarily at gene enhancers (https://doi.org/10.3389/fgene.2022.826594)	Aberrant repression of genes involved in immune signaling such as CD40, IL10-IL6, and NFkB signaling

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

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Links

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References

1. https://tumourclassification.iarc.who.int/chaptercontent/63/149
2. Liu H, Xu-Monette ZY, Tang G, Wang W, Kim Y, Yuan J, Li Y, Chen W, Li Y, Fedoriw GY, Zhu F, Fang X, Luedke C, Medeiros LJ, Young KH & Hu S (2022) Histopathology 80, 575–588. https://doi.org/10.1111/his.14585 EBV+ high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a multi-institutional study
3. Frontzek, F., Staiger, A.M., Wullenkord, R. et al. Molecular profiling of EBV associated diffuse large B-cell lymphoma. Leukemia 37, 670–679 (2023). https://doi.org/10.1038/s41375-022-01804-w
4. Zhang, Yuxiu MD*; Li, Anqi MD, PhD*; Li, Yimin MD, PhD*; Ouyang, Binshen MD, PhD*; Wang, Xuan MD, PhD*; Zhang, Lei MSc*; Xu, Haimin BSMT*; Gu, Yijin MSc*; Lu, Xinyuan MD, PhD†; Dong, Lei MD, PhD*; Yi, Hongmei MD, PhD*; Wang, Chaofu MD, PhD*. Clinicopathological and Molecular Characteristics of Rare EBV-associated Diffuse Large B-cell Lymphoma With IRF4 Rearrangement. The American Journal of Surgical Pathology 48(11):p 1341-1348, November 2024. | DOI: 10.1097/PAS.0000000000002301
5. Gebauer, N., Künstner, A., Ketzer, J. et al. Genomic insights into the pathogenesis of Epstein–Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing. Blood Cancer J. 11, 102 (2021). https://doi.org/10.1038/s41408-021-00493-5
6. Takahashi, T., Sawada, K., Yamashita, T., Yamamoto, W., Iijima, Y., Adachi, A., Kashimura, M., Tabayashi, T., Kizaki, M., Kaneko, T., Tamaru, J.-i., Higashi, M. and Momose, S. (2025), Genetic Profiling Reveals the Distinctions Among MTX-Associated DLBCL, EBV-Positive Mucocutaneous Ulcer, and EBV + DLBCL. Cancer Sci, 116: 2306-2316. https://doi.org/10.1111/cas.70111
7. Liau, N.P.D., Laktyushin, A., Lucet, I.S. et al. The molecular basis of JAK/STAT inhibition by SOCS1. Nat Commun 9, 1558 (2018). https://doi.org/10.1038/s41467-018-04013-1
8. Zhang XY, Xing TY, Hua W, Li Y, Kong YL, Pan BH, Zhang XY, Wu JZ, Shen HR, Yin H, Wang L, Li JY, Gao R, Liang JH, Xu W. Prognostic Role of SOCS1 Mutations in Diffuse Large B-Cell Lymphoma. Cancer Res Treat. ;0.0. doi: 10.4143/crt.2025.420
9. Carpenter, R. L., & Lo, H.-W. (2014). STAT3 Target Genes Relevant to Human Cancers. Cancers, 6(2), 897-925. https://doi.org/10.3390/cancers6020897
10. Mondello P, Ansell SM and Nowakowski GS (2022) Immune Epigenetic Crosstalk Between Malignant B Cells and the Tumor Microenvironment in B Cell Lymphoma. Front. Genet. 13:826594. doi: 10.3389/fgene.2022.826594 (KMT2D) not able to create this citation

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

*Citation of this Page: “EBV-positive diffuse large B-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/25/2026, https://ccga.io/index.php/HAEM5:EBV-positive_diffuse_large_B-cell_lymphoma.