View source for HAEM5:EBV-positive diffuse large B-cell lymphoma

{{DISPLAYTITLE:EBV-positive diffuse large B-cell lymphoma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

{{Under Construction}}

<span style="color:#0070C0">(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 [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)</span>

==Primary Author(s)*==


Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
==WHO Classification of Disease==

{| class="wikitable"
!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==

{| class="wikitable"
|+
|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.<ref name=":4">{{Cite journal|title=BlueBooksOnline|url=https://tumourclassification.iarc.who.int/chaptercontent/63/149}}</ref> 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<ref>{{Cite journal|last=Liu|first=Hui|last2=Xu-Monette|first2=Zijun Y|last3=Tang|first3=Guilin|last4=Wang|first4=Wei|last5=Kim|first5=Young|last6=Yuan|first6=Ji|last7=Li|first7=Yu|last8=Chen|first8=Weina|last9=Li|first9=Yanping|date=2022|title=EBV+ high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a multi-institutional study|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/his.14585|journal=Histopathology|language=en|volume=80|issue=3|pages=575–588|doi=10.1111/his.14585|issn=1365-2559}}</ref><ref name=":1">{{Cite journal|last=Frontzek|first=Fabian|last2=Staiger|first2=Annette M.|last3=Wullenkord|first3=Ramona|last4=Grau|first4=Michael|last5=Zapukhlyak|first5=Myroslav|last6=Kurz|first6=Katrin S.|last7=Horn|first7=Heike|last8=Erdmann|first8=Tabea|last9=Fend|first9=Falko|date=2023-03|title=Molecular profiling of EBV associated diffuse large B-cell lymphoma|url=https://www.nature.com/articles/s41375-022-01804-w|journal=Leukemia|language=en|volume=37|issue=3|pages=670–679|doi=10.1038/s41375-022-01804-w|issn=1476-5551|pmc=9991915|pmid=36604606}}</ref>. 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<ref name=":0">{{Cite journal|last=Zhang|first=Yuxiu|last2=Li|first2=Anqi|last3=Li|first3=Yimin|last4=Ouyang|first4=Binshen|last5=Wang|first5=Xuan|last6=Zhang|first6=Lei|last7=Xu|first7=Haimin|last8=Gu|first8=Yijin|last9=Lu|first9=Xinyuan|date=2024-11|title=Clinicopathological and Molecular Characteristics of Rare EBV-associated Diffuse Large B-cell Lymphoma With IRF4 Rearrangement|url=https://journals.lww.com/10.1097/PAS.0000000000002301|journal=American Journal of Surgical Pathology|language=en|volume=48|issue=11|pages=1341–1348|doi=10.1097/PAS.0000000000002301|issn=0147-5185}}</ref>. ''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<ref name=":0" /> Clinically, morphologically as well as at the molecular level, EBV+DLBCL-''IRF4''-R resemble and behave like EBV+DLBCL<ref name=":0" />
{| class="wikitable sortable"
|-
!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.

{| class="wikitable sortable"
|-
!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%)<ref name=":2" />, 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 '''''ANKRD11''1''' and '''''NOTCH2''''' mutations, suggesting a distinct pathogenic mechanism. Multiple focal amplifications have been reported<ref name=":1" />, 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<ref name=":1" />. Additional immune-escape and oncogenic amplifications include '''1q24.3 (FASL)''' (22%), '''11q24.3 (ETS1/FLI1)''' (20%), and '''2q31.3''' containing the lncRNA ''SChLAP1''<ref name=":1" />. Deletions are less common but include broad losses of '''18p/18q''' and a recurrent focal deletion at '''11p15.3''' impacting the tumor-suppressor ''DKK3''<ref name=":1" />. These structural alterations did not correspond to distinct gene-expression profiles.
{| class="wikitable sortable"
|-
!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<ref name=":2" />
|Tumor-suppressor genes: ''PRDM1 and A20''<ref name=":2" />
|Common<ref name=":2" />
|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<ref name=":6">{{Cite journal|last=Xia|first=Y|last2=Xu-Monette|first2=Z Y|last3=Tzankov|first3=A|last4=Li|first4=X|last5=Manyam|first5=G C|last6=Murty|first6=V|last7=Bhagat|first7=G|last8=Zhang|first8=S|last9=Pasqualucci|first9=L|date=2017-03|title=Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma|url=https://www.nature.com/articles/leu2016243|journal=Leukemia|language=en|volume=31|issue=3|pages=625–636|doi=10.1038/leu.2016.243|issn=0887-6924|pmc=5837859|pmid=27568520}}</ref>
|-
|6p25.3 amplifications<ref name=":1" />
|5 different genes including the oncogene ''IRF4'' are located<ref name=":1" />
|Common<ref name=":1" />
|May be D
|No
|
|-
|9p24.1 amplifications<ref name=":1" />
|''PD-L1/PD-L2'' and ''JAK2''<ref name=":1" /> 
|Recurrent<ref name=":1" />
|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<ref name=":1" /><ref>{{Cite journal|last=Ibrahim|first=Eman Mohamad|last2=Refat|first2=Sherine|last3=El-Ashwah|first3=Shaimaa|last4=Fahmi|first4=Maryan Waheeb|last5=Ibrahiem|first5=Afaf Taha|date=2023-05-08|title=Programmed death ligand 1 expression in diffuse large B cell lymphoma: correlation with clinicopathological prognostic factors|url=https://jenci.springeropen.com/articles/10.1186/s43046-023-00171-6|journal=Journal of the Egyptian National Cancer Institute|language=en|volume=35|issue=1|doi=10.1186/s43046-023-00171-6|issn=2589-0409}}</ref><ref>{{Cite journal|last=Kataoka|first=Keisuke|last2=Miyoshi|first2=Hiroaki|last3=Sakata|first3=Seiji|last4=Dobashi|first4=Akito|last5=Couronné|first5=Lucile|last6=Kogure|first6=Yasunori|last7=Sato|first7=Yasuharu|last8=Nishida|first8=Kenji|last9=Gion|first9=Yuka|date=2019-07|title=Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas|url=https://www.nature.com/articles/s41375-019-0380-5|journal=Leukemia|language=en|volume=33|issue=7|pages=1687–1699|doi=10.1038/s41375-019-0380-5|issn=0887-6924|pmc=6755969|pmid=30683910}}</ref>
|}
==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.<ref name=":4" /><ref name=":1" /><ref name=":2" /> 

According to the most recent literature,<ref name=":2" /> 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.<ref name=":4" /><ref name=":2" />

Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>
{| class="wikitable sortable"
|-
!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''<ref name=":1" /><ref name=":2">{{Cite journal|last=Gebauer|first=Niklas|last2=Künstner|first2=Axel|last3=Ketzer|first3=Julius|last4=Witte|first4=Hanno M.|last5=Rausch|first5=Tobias|last6=Benes|first6=Vladimir|last7=Zimmermann|first7=Jürgen|last8=Gebauer|first8=Judith|last9=Merz|first9=Hartmut|date=2021-05-26|title=Genomic insights into the pathogenesis of Epstein–Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing|url=https://www.nature.com/articles/s41408-021-00493-5|journal=Blood Cancer Journal|language=en|volume=11|issue=5|pages=102|doi=10.1038/s41408-021-00493-5|issn=2044-5385|pmc=8155002|pmid=34039950}}</ref><ref name=":3">{{Cite journal|last=Takahashi|first=Takumi|last2=Sawada|first2=Keisuke|last3=Yamashita|first3=Takahisa|last4=Yamamoto|first4=Wataru|last5=Iijima|first5=Yosuke|last6=Adachi|first6=Akiko|last7=Kashimura|first7=Makoto|last8=Tabayashi|first8=Takayuki|last9=Kizaki|first9=Masahiro|date=2025|title=Genetic Profiling Reveals the Distinctions Among MTX-Associated DLBCL, EBV-Positive Mucocutaneous Ulcer, and EBV + DLBCL|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/cas.70111|journal=Cancer Science|language=en|volume=116|issue=8|pages=2306–2316|doi=10.1111/cas.70111|issn=1349-7006|pmc=12317404|pmid=40458922}}</ref>

<br />
|Loss of function aberration in the SH2 domain<ref name=":1" />
|Tumor Suppressor gene<ref name=":7">{{Cite journal|last=Liau|first=Nicholas P. D.|last2=Laktyushin|first2=Artem|last3=Lucet|first3=Isabelle S.|last4=Murphy|first4=James M.|last5=Yao|first5=Shenggen|last6=Whitlock|first6=Eden|last7=Callaghan|first7=Kimberley|last8=Nicola|first8=Nicos A.|last9=Kershaw|first9=Nadia J.|date=2018-04-19|title=The molecular basis of JAK/STAT inhibition by SOCS1|url=https://www.nature.com/articles/s41467-018-04013-1|journal=Nature Communications|language=en|volume=9|issue=1|pages=1558|doi=10.1038/s41467-018-04013-1|issn=2041-1723|pmc=5908791|pmid=29674694}}</ref>
|Common<ref name=":1" /><ref name=":2" /><ref name=":3" />
|P, T
|<span class="blue-text">EXAMPLE:</span> 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.<ref>{{Cite journal|last=Zhang|first=Xin-Yi|last2=Xing|first2=Tong-Yao|last3=Hua|first3=Wei|last4=Li|first4=Yue|last5=Kong|first5=Yi-Lin|last6=Pan|first6=Bi-Hui|last7=Zhang|first7=Xin-Yu|last8=Wu|first8=Jia-Zhu|last9=Shen|first9=Hao-Rui|date=2025-08-31|title=Prognostic Role of SOCS1 Mutations in Diffuse Large B-Cell Lymphoma|url=https://www.e-crt.org/journal/view.php?doi=10.4143/crt.2025.420|journal=Cancer Research and Treatment|language=English|doi=10.4143/crt.2025.420|issn=1598-2998}}</ref>
|-
|''STAT3''<ref name=":1" /><ref name=":2" />
<br />
|Activating missense mutations<ref name=":1" /> 
|Oncogene/ Tumor suppressor gene<ref>{{Cite journal|last=Carpenter|first=Richard|last2=Lo|first2=Hui-Wen|date=2014-04-16|title=STAT3 Target Genes Relevant to Human Cancers|url=https://www.mdpi.com/2072-6694/6/2/897|journal=Cancers|language=en|volume=6|issue=2|pages=897–925|doi=10.3390/cancers6020897|issn=2072-6694|pmc=4074809|pmid=24743777}}</ref>
|Common<ref name=":1" /><ref name=":2" />
|T
|
|STAT3 is an effective molecular target for ABC-like DLBCL therapy<ref>{{Cite journal|last=Scuto|first=Anna|last2=Kujawski|first2=Maciej|last3=Kowolik|first3=Claudia|last4=Krymskaya|first4=Ludmila|last5=Wang|first5=Lin|last6=Weiss|first6=Lawrence M.|last7=DiGiusto|first7=David|last8=Yu|first8=Hua|last9=Forman|first9=Stephen|date=2011-05-01|title=STAT3 Inhibition Is a Therapeutic Strategy for ABC-like Diffuse Large B-Cell Lymphoma|url=https://aacrjournals.org/cancerres/article/71/9/3182/575555/STAT3-Inhibition-Is-a-Therapeutic-Strategy-for-ABC|journal=Cancer Research|language=en|volume=71|issue=9|pages=3182–3188|doi=10.1158/0008-5472.CAN-10-2380|issn=0008-5472}}</ref>
|-
|''KMT2D''<ref name=":1" /><ref name=":2" /><ref name=":5">{{Cite journal|last=Zhou|first=Yangying|last2=Xu|first2=Zhijie|last3=Lin|first3=Wei|last4=Duan|first4=Yumei|last5=Lu|first5=Can|last6=Liu|first6=Wei|last7=Su|first7=Weiping|last8=Yan|first8=Yuanliang|last9=Liu|first9=Huan|date=2019-07-25|title=Comprehensive Genomic Profiling of EBV-Positive Diffuse Large B-cell Lymphoma and the Expression and Clinicopathological Correlations of Some Related Genes|url=https://www.frontiersin.org/article/10.3389/fonc.2019.00683/full|journal=Frontiers in Oncology|volume=9|doi=10.3389/fonc.2019.00683|issn=2234-943X|pmc=6669985|pmid=31403034}}</ref>
|Inactivating mutations
|Tumor Suppressor Gene<ref>{{Cite journal|title=OncoKB™ - MSK's Precision Oncology Knowledge Base|url=https://www.oncokb.org/|language=en}}</ref>
|Common<ref name=":1" /><ref name=":2" /><ref name=":5" />
|D
|No
|Several tumor suppressor genes such as ''TNFAIP3'' and ''SOCS3'' also become silenced upon ''KMT2D'' loss of function<ref>{{Cite journal|last=Ortega-Molina|first=Ana|last2=Boss|first2=Isaac W|last3=Canela|first3=Andres|last4=Pan|first4=Heng|last5=Jiang|first5=Yanwen|last6=Zhao|first6=Chunying|last7=Jiang|first7=Man|last8=Hu|first8=Deqing|last9=Agirre|first9=Xabier|date=2015-10|title=The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development|url=https://www.nature.com/articles/nm.3943|journal=Nature Medicine|language=en|volume=21|issue=10|pages=1199–1208|doi=10.1038/nm.3943|issn=1078-8956|pmc=4676270|pmid=26366710}}</ref>.  Targeting KDM5 demethylases counteracts ''KMT2D'' loss of function in DLBCL, which can open the opportunity for novel combination targeted therapies.<ref>{{Cite journal|last=Heward|first=James|last2=Koniali|first2=Lola|last3=D’Avola|first3=Annalisa|last4=Close|first4=Karina|last5=Yeomans|first5=Alison|last6=Philpott|first6=Martin|last7=Dunford|first7=James|last8=Rahim|first8=Tahrima|last9=Al Seraihi|first9=Ahad F.|date=2021-08-05|title=KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas|url=https://ashpublications.org/blood/article/138/5/370/475650/KDM5-inhibition-offers-a-novel-therapeutic|journal=Blood|language=en|volume=138|issue=5|pages=370–381|doi=10.1182/blood.2020008743|issn=0006-4971|pmc=8351530|pmid=33786580}}</ref>
|-
|''CCR6''<ref name=":2" />
|
|
|
|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.<ref name=":2" /><ref>{{Cite journal|last=Moody|first=Sarah|last2=Thompson|first2=Joe Sneath|last3=Chuang|first3=Shih-Sung|last4=Liu|first4=Hongxiang|last5=Raderer|first5=Markus|last6=Vassiliou|first6=George|last7=Wlodarska|first7=Iwona|last8=Wu|first8=Fangtian|last9=Cogliatti|first9=Sergio|date=2018-08|title=Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2018.191601|journal=Haematologica|language=en|volume=103|issue=8|pages=1329–1336|doi=10.3324/haematol.2018.191601|issn=0390-6078|pmc=6068028|pmid=29674500}}</ref>
|-
|''CCR7''<ref name=":2" />
|
|
|
|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.<ref name=":2" /><ref>{{Cite journal|last=Kocks|first=Jessica R|last2=Adler|first2=Heiko|last3=Danzer|first3=Heike|last4=Hoffmann|first4=Katharina|last5=Jonigk|first5=Danny|last6=Lehmann|first6=Ulrich|last7=Förster|first7=Reinhold|date=2009-06-01|title=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|url=https://academic.oup.com/jimmunol/article/182/11/6861/8007100|journal=The Journal of Immunology|language=en|volume=182|issue=11|pages=6861–6869|doi=10.4049/jimmunol.0801826|issn=1550-6606}}</ref>
|-
|''DAPK1''<ref name=":2" />
|
|
|
|D, P
|No
|Oncogenic ''DAPK1'' mutations appear to be '''unique/ exclusive to EBV+ DLBCL'''<ref name=":2" />. Prior studies have shown poor prognosis associated with hypermethylation - loss of function mutations in ''DAPK1'' and may similarly contribute to adverse prognosis.<ref name=":6" />
|-
|''TNFRSF21''<ref name=":2" />
|
|
|
|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<ref>{{Cite journal|last=Wang|first=Ming|last2=Zhang|first2=Shaowei|last3=Chuang|first3=Shih-Sung|last4=Ashton-Key|first4=Margaret|last5=Ochoa|first5=Eguzkine|last6=Bolli|first6=Niccolo|last7=Vassiliou|first7=George|last8=Gao|first8=Zifen|last9=Du|first9=Ming-Qing|date=2017-03-14|title=Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling|url=https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.14846|journal=Oncotarget|language=en|volume=8|issue=11|pages=17763–17770|doi=10.18632/oncotarget.14846|issn=1949-2553|pmc=5392284|pmid=28148900}}</ref>
|-
|''CSNK2B''<ref name=":2" />
|
|
|
|D
|No
|''CSNK2B'', another alteration uniquely seen in EBV⁺ DLBCL, remains poorly characterized and its oncogenic role is not yet well understood.<ref name=":2" />
|-
|''YY1''<ref name=":2" />
|
|
|
|D
|No
|''YY1'' is a known oncogenic driver in DLBCL, where its overexpression promotes B-cell transformation and tumor progression, independent of EBV status.<ref name=":2" />
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], 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 <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|''SOCS1;'' Inactivating mutations<ref name=":1" />
|JAK-STAT and interferon gamma (INFγ) signaling pathways
|Activation of the JAK-STAT INFγ signaling pathways<ref name=":1" /><ref name=":7" />
|-
|''STAT3 and STAT6''; Activating mutations<ref name=":1" /><ref name=":8">{{Cite journal|last=Zeinalzadeh|first=Elham|last2=Valerievich Yumashev|first2=Alexey|last3=Rahman|first3=Heshu Sulaiman|last4=Marofi|first4=Faroogh|last5=Shomali|first5=Navid|last6=Kafil|first6=Hossein Samadi|last7=Solali|first7=Saeed|last8=Sajjadi-Dokht|first8=Mehdi|last9=Vakili-Samiani|first9=Sajjad|date=2021-12-21|title=RETRACTED: The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics|url=https://www.frontiersin.org/articles/10.3389/fgene.2021.703883/full|journal=Frontiers in Genetics|volume=12|doi=10.3389/fgene.2021.703883|issn=1664-8021|pmc=8725977|pmid=34992627}}</ref>
|Normal cellular events: Survival, proliferation, and differentiation<ref name=":8" />
|Tumor cell survival, proliferation, and invasion<ref name=":8" /><ref>{{Cite journal|last=Kennedy|first=Ruth|last2=Klein|first2=Ulf|date=2018-10-30|title=Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies|url=https://www.mdpi.com/2073-4409/7/11/189|journal=Cells|language=en|volume=7|issue=11|pages=189|doi=10.3390/cells7110189|issn=2073-4409|pmc=6262606|pmid=30380749}}</ref>
|-
|''TNFAIP3'' (A20) and ''MAP3K14'' (NIK); Inactivating mutations
|Negative regulation of NF-κB pathway<ref name=":9">{{Cite journal|last=Pasqualucci|first=Laura|last2=Dalla-Favera|first2=Riccardo|date=2018-05-24|title=Genetics of diffuse large B-cell lymphoma|url=https://ashpublications.org/blood/article/131/21/2307/37115/Genetics-of-diffuse-large-Bcell-lymphoma|journal=Blood|language=en|volume=131|issue=21|pages=2307–2319|doi=10.1182/blood-2017-11-764332|issn=0006-4971|pmc=5969374|pmid=29666115}}</ref>
|Abnormal and prolonged activation of the NF-κB pathway<ref name=":9" />
|-
|''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 
|-
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|}
==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==

# https://tumourclassification.iarc.who.int/chaptercontent/63/149
# 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. <nowiki>https://doi.org/10.1111/his.14585</nowiki> EBV+ high-grade B cell lymphoma with ''MYC'' and ''BCL2'' and/or ''BCL6'' rearrangements: a multi-institutional study 
# Frontzek, F., Staiger, A.M., Wullenkord, R. ''et al.'' Molecular profiling of EBV associated diffuse large B-cell lymphoma. ''Leukemia'' 37, 670–679 (2023). <nowiki>https://doi.org/10.1038/s41375-022-01804-w</nowiki>
# 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 
# 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). <nowiki>https://doi.org/10.1038/s41408-021-00493-5</nowiki> 
# 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. <nowiki>https://doi.org/10.1111/cas.70111</nowiki>
# 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). <nowiki>https://doi.org/10.1038/s41467-018-04013-1</nowiki> 
# 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
# Carpenter, R. L., & Lo, H.-W. (2014). STAT3 Target Genes Relevant to Human Cancers. ''Cancers'', ''6''(2), 897-925. <nowiki>https://doi.org/10.3390/cancers6020897</nowiki>
# 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 '''<u>(KMT2D) not able to create this citation</u>'''
<references />

==Notes==
<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] 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):  

        
<nowiki>*</nowiki>''Citation of this Page'': “EBV-positive diffuse large B-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:EBV-positive_diffuse_large_B-cell_lymphoma</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases E]]