EBV-positive diffuse large B-cell lymphoma

From Compendium of Cancer Genome Aberrations
Jump to navigation Jump to search

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)*

Put your text here (EXAMPLE: Jane Smith, PhD)

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.[1] 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[2][3]. 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[4]. 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[4] Clinically, morphologically as well as at the molecular level, EBV+DLBCL-IRF4-R resemble and behave like EBV+DLBCL[4]

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%)[5], 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[3], 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[3]. Additional immune-escape and oncogenic amplifications include 1q24.3 (FASL) (22%), 11q24.3 (ETS1/FLI1) (20%), and 2q31.3 containing the lncRNA SChLAP1[3]. Deletions are less common but include broad losses of 18p/18q and a recurrent focal deletion at 11p15.3 impacting the tumor-suppressor DKK3[3]. 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[5] Tumor-suppressor genes: PRDM1 and A20[5] Common[5] 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[6]
6p25.3 amplifications[3] 5 different genes including the oncogene IRF4 are located[3] Common[3] May be D No
9p24.1 amplifications[3] PD-L1/PD-L2 and JAK2[3] Recurrent[3] 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[3][7][8]

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.[1][3][5]

According to the most recent literature,[5] 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.[1][5]

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[3][5][9]


Loss of function aberration in the SH2 domain[3] Tumor Suppressor gene[10] Common[3][5][9] 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.[11]
STAT3[3][5]


Activating missense mutations[3] Oncogene/ Tumor suppressor gene[12] Common[3][5] T STAT3 is an effective molecular target for ABC-like DLBCL therapy[13]
KMT2D[3][5][14] Tumor Suppressor Gene[15] Common[3][5][14] D No
CCR6[5] 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.[5][16]
CCR7[5] 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.[5][17]
DAPK1[5] D, P No Oncogenic DAPK1 mutations appear to be unique/ exclusive to EBV+ DLBCL[5]. Prior studies have shown poor prognosis associated with hypermethylation - loss of function mutations in DAPK1 and may similarly contribute to adverse prognosis.[6]
TNFRSF21[5] 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[18]
CSNK2B[5] D No CSNK2B, another alteration uniquely seen in EBV⁺ DLBCL, remains poorly characterized and its oncogenic role is not yet well understood.[5]
YY1[5] D No YY1 is a known oncogenic driver in DLBCL, where its overexpression promotes B-cell transformation and tumor progression, independent of EBV status.[5]

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

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
SOCS1; Inactivating mutations[3] JAK-STAT and interferon gamma (INFγ) signaling pathways Activation of the JAK-STAT INFγ signaling pathways[3][10]
STAT3 and STAT6; Activating mutations[3][19] Normal cellular events: Survival, proliferation, and differentiation[19] Tumor cell survival, proliferation, and invasion[19]
EXAMPLE: KMT2C and ARID1A; Inactivating mutations EXAMPLE: Histone modification, chromatin remodeling EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

Put your text here (Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.)

Familial Forms

Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)

Additional Information

Put your text here

Links

Put a link here or anywhere appropriate in this page (Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "http://www." portion.)

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

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 12/2/2025, https://ccga.io/index.php/HAEM5:EBV-positive_diffuse_large_B-cell_lymphoma.

  1. ↑ 1.0 1.1 1.2 "BlueBooksOnline".
  2. ↑ Liu, Hui; et al. (2022). "EBV+ high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a multi-institutional study". Histopathology. 80 (3): 575–588. doi:10.1111/his.14585. ISSN 1365-2559.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 Frontzek, Fabian; et al. (2023-03). "Molecular profiling of EBV associated diffuse large B-cell lymphoma". Leukemia. 37 (3): 670–679. doi:10.1038/s41375-022-01804-w. ISSN 1476-5551. PMC 9991915 Check |pmc= value (help). PMID 36604606 Check |pmid= value (help). Check date values in: |date= (help)
  4. ↑ 4.0 4.1 4.2 Zhang, Yuxiu; et al. (2024-11). "Clinicopathological and Molecular Characteristics of Rare EBV-associated Diffuse Large B-cell Lymphoma With IRF4 Rearrangement". American Journal of Surgical Pathology. 48 (11): 1341–1348. doi:10.1097/PAS.0000000000002301. ISSN 0147-5185. Check date values in: |date= (help)
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 5.21 5.22 5.23 Gebauer, Niklas; et al. (2021-05-26). "Genomic insights into the pathogenesis of Epstein–Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing". Blood Cancer Journal. 11 (5): 102. doi:10.1038/s41408-021-00493-5. ISSN 2044-5385. PMC 8155002 Check |pmc= value (help). PMID 34039950 Check |pmid= value (help).
  6. ↑ 6.0 6.1 Xia, Y; et al. (2017-03). "Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma". Leukemia. 31 (3): 625–636. doi:10.1038/leu.2016.243. ISSN 0887-6924. PMC 5837859. PMID 27568520. Check date values in: |date= (help)
  7. ↑ Ibrahim, Eman Mohamad; et al. (2023-05-08). "Programmed death ligand 1 expression in diffuse large B cell lymphoma: correlation with clinicopathological prognostic factors". Journal of the Egyptian National Cancer Institute. 35 (1). doi:10.1186/s43046-023-00171-6. ISSN 2589-0409.
  8. ↑ Kataoka, Keisuke; et al. (2019-07). "Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas". Leukemia. 33 (7): 1687–1699. doi:10.1038/s41375-019-0380-5. ISSN 0887-6924. PMC 6755969. PMID 30683910. Check date values in: |date= (help)
  9. ↑ 9.0 9.1 Takahashi, Takumi; et al. (2025). "Genetic Profiling Reveals the Distinctions Among MTX-Associated DLBCL, EBV-Positive Mucocutaneous Ulcer, and EBV + DLBCL". Cancer Science. 116 (8): 2306–2316. doi:10.1111/cas.70111. ISSN 1349-7006. PMC 12317404 Check |pmc= value (help). PMID 40458922 Check |pmid= value (help).
  10. ↑ 10.0 10.1 Liau, Nicholas P. D.; et al. (2018-04-19). "The molecular basis of JAK/STAT inhibition by SOCS1". Nature Communications. 9 (1): 1558. doi:10.1038/s41467-018-04013-1. ISSN 2041-1723. PMC 5908791. PMID 29674694.
  11. ↑ Zhang, Xin-Yi; et al. (2025-08-31). "Prognostic Role of SOCS1 Mutations in Diffuse Large B-Cell Lymphoma". Cancer Research and Treatment. doi:10.4143/crt.2025.420. ISSN 1598-2998.
  12. ↑ Carpenter, Richard; et al. (2014-04-16). "STAT3 Target Genes Relevant to Human Cancers". Cancers. 6 (2): 897–925. doi:10.3390/cancers6020897. ISSN 2072-6694. PMC 4074809. PMID 24743777.
  13. ↑ Scuto, Anna; et al. (2011-05-01). "STAT3 Inhibition Is a Therapeutic Strategy for ABC-like Diffuse Large B-Cell Lymphoma". Cancer Research. 71 (9): 3182–3188. doi:10.1158/0008-5472.CAN-10-2380. ISSN 0008-5472.
  14. ↑ 14.0 14.1 Zhou, Yangying; et al. (2019-07-25). "Comprehensive Genomic Profiling of EBV-Positive Diffuse Large B-cell Lymphoma and the Expression and Clinicopathological Correlations of Some Related Genes". Frontiers in Oncology. 9. doi:10.3389/fonc.2019.00683. ISSN 2234-943X. PMC 6669985. PMID 31403034.
  15. ↑ "OncoKB™ - MSK's Precision Oncology Knowledge Base".
  16. ↑ Moody, Sarah; et al. (2018-08). "Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites". Haematologica. 103 (8): 1329–1336. doi:10.3324/haematol.2018.191601. ISSN 0390-6078. PMC 6068028. PMID 29674500. Check date values in: |date= (help)
  17. ↑ Kocks, Jessica R; et al. (2009-06-01). "Chemokine Receptor CCR7 Contributes to a Rapid and Efficient Clearance of Lytic Murine γ-Herpes Virus 68 from the Lung, Whereas Bronchus-Associated Lymphoid Tissue Harbors Virus during Latency". The Journal of Immunology. 182 (11): 6861–6869. doi:10.4049/jimmunol.0801826. ISSN 1550-6606.
  18. ↑ Wang, Ming; et al. (2017-03-14). "Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling". Oncotarget. 8 (11): 17763–17770. doi:10.18632/oncotarget.14846. ISSN 1949-2553. PMC 5392284. PMID 28148900.
  19. ↑ 19.0 19.1 19.2 Zeinalzadeh, Elham; et al. (2021-12-21). "RETRACTED: The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics". Frontiers in Genetics. 12. doi:10.3389/fgene.2021.703883. ISSN 1664-8021. PMC 8725977 Check |pmc= value (help). PMID 34992627 Check |pmid= value (help).
Retrieved from "https://test.ccga.io/index.php?title=HAEM5:EBV-positive_diffuse_large_B-cell_lymphoma&oldid=19853"