Compendium of Cancer Genome Aberrations

HAEM5:EBV-positive diffuse large B-cell lymphoma: Difference between revisions

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<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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 to a table, click within the table and select the > symbol that appears to be given options. 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>
<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)*==
==Primary Author(s)*==


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


__TOC__
{| 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
|}


==Cancer Category / Type==
==Related Terminology==


Put your text here
==Cancer Sub-Classification / Subtype==
Put your text here
==Definition / Description of Disease==
Put your text here <span style="color:#0070C0">(''Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories, diagnostic criteria if applicable, and differential diagnosis if applicable. Other classifications can be referenced for comparison.'') </span>
==Synonyms / Terminology==
Put your text here <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>
==Epidemiology / Prevalence==
Put your text here
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
|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
|}


<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
==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" />
<span class="blue-text">EXAMPLE:</span> Fatigue
{| class="wikitable sortable"
 
<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
|<span class="blue-text">EXAMPLE:</span> Cytopenias
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
 
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|}
|}
 
==Individual Region Genomic Gain/Loss/LOH==
==Sites of Involvement==
None reported so far.
 
Put your text here <span style="color:#0070C0">(''Instruction: Indicate physical sites; <span class="blue-text">EXAMPLE:</span> nodal, extranodal, bone marrow'') </span>
 
==Morphologic Features==
 
Put your text here
 
==Immunophenotype==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!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"
|-
|-
|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
!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
|-
|-
|Positive (subset)||<span class="blue-text">EXAMPLE:</span> CD2
|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>
|-
|-
|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
|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
|
|-
|-
|Negative (subset)||<span class="blue-text">EXAMPLE:</span> CD4
|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" />


==Chromosomal Rearrangements (Gene Fusions)==
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


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"
{| class="wikitable sortable"
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!Diagnostic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
|''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>
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
|Yes
|No
|Yes
|<span class="blue-text">EXAMPLE:</span>


The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
<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>
==Individual Region Genomic Gain / Loss / LOH==
|Common<ref name=":1" /><ref name=":2" /><ref name=":3" />
 
|P, T
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>
|<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>
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
|''STAT3''<ref name=":1" /><ref name=":2" />
!Diagnostic Significance (Yes, No or Unknown)
<br />
!Prognostic Significance (Yes, No or Unknown)
|Activating missense mutations<ref name=":1" />
!Therapeutic Significance (Yes, No or Unknown)
|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>
!Notes
|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>
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|''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
7
|Tumor Suppressor Gene<ref>{{Cite journal|title=OncoKB™ - MSK's Precision Oncology Knowledge Base|url=https://www.oncokb.org/|language=en}}</ref>
|<span class="blue-text">EXAMPLE:</span> Loss
|Common<ref name=":1" /><ref name=":2" /><ref name=":5" />
|<span class="blue-text">EXAMPLE:</span>
|D
 
chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>
 
chr7
|Yes
|Yes
|No
|No
|<span class="blue-text">EXAMPLE:</span>
|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>
 
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|''CCR6''<ref name=":2" />
 
|
8
|
|<span class="blue-text">EXAMPLE:</span> Gain
|
|<span class="blue-text">EXAMPLE:</span>
|D
 
chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>
 
chr8
|No
|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
|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
|No
|<span class="blue-text">EXAMPLE:</span>
|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" />
 
Common recurrent secondary finding for t(8;21) (add reference).
|}
==Characteristic Chromosomal Patterns==
 
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.'')</span>
 
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
|''TNFRSF21''<ref name=":2" />
!Diagnostic Significance (Yes, No or Unknown)
|
!Prognostic Significance (Yes, No or Unknown)
|
!Therapeutic Significance (Yes, No or Unknown)
|
!Notes
|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>
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|''CSNK2B''<ref name=":2" />
 
|
Co-deletion of 1p and 18q
|
|Yes
|
|No
|D
|No
|No
|<span class="blue-text">EXAMPLE:</span>
|''CSNK2B'', another alteration uniquely seen in EBV⁺ DLBCL, remains poorly characterized and its oncogenic role is not yet well understood.<ref name=":2" />
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
==Gene Mutations (SNV / INDEL)==
 
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 and common as well as either disease defining and/or clinically significant. Can include references 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. Do not delete table.'') </span>
 
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
|''YY1''<ref name=":2" />
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations
 
<span class="blue-text">EXAMPLE:</span>
 
EGFR; Exon 20 mutations
 
<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> TSG
|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
 
<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|<span class="blue-text">EXAMPLE:</span> EGFR amplification
|
|
|
|
|
|
|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
|D
<br />
|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 cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|}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==
==Epigenomic Alterations==
 
None identified so far.
Put your text here
 
==Genes and Main Pathways Involved==
==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>
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
|''SOCS1;'' Inactivating mutations<ref name=":1" />
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|JAK-STAT and interferon gamma (INFγ) signaling pathways
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|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" />
|-
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|''KMT2D and KMT2C;'' Loss of function mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|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)
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Aberrant repression of genes involved in immune signaling such as CD40, IL10-IL6, and NFkB signaling
|-
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
|
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
 
Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
Put your text here
 
==Familial Forms==
==Familial Forms==
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
==Additional Information==
==Additional Information==
Put your text here
Put your text here
==Links==
==Links==


Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the 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 "<nowiki>http://www</nowiki>." portion.'')</span>
Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''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 "<nowiki>http://www</nowiki>." portion.'')</span>


==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />


'''EXAMPLE Book'''
# 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 />


#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
==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.


==Notes==
Prior Author(s): 
<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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
       
<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>.
<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]]
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases E]]
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