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

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 ==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 like '''''PRDM1 and A20''''', which play key roles in B-cell lymphoma development''',''' although these cases show fewer '''''ANKRD11''1''' and '''''NOTCH2''''' mutations. 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. 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.
+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"
 |-
@@ Line 80: / Line 80: @@
 |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>{{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>
+|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" />
@@ Line 93: / Line 93: @@
 |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)==
@@ Line 114: / Line 114: @@
 <br />
 |Loss of function aberration in the SH2 domain<ref name=":1" />
-|Tumor Suppressor gene<ref>{{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>
+|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
@@ Line 130: / Line 130: @@
 |-
 |''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==
@@ Line 153: / Line 193: @@
 !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>
 |-
-|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
+|''TNFAIP3'' (A20) and ''MAP3K14'' (NIK); Inactivating mutations
-|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
+|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>
-|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
+|Abnormal and prolonged activation of the NF-κB pathway<ref name=":9" />
 |-
-|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
+|''KMT2D and KMT2C;'' Loss of function mutations
-|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
+|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> Abnormal gene expression program
+|Aberrant repression of genes involved in immune signaling such as CD40, IL10-IL6, and NFkB signaling
 |-
 |
@@ Line 190: / Line 234: @@
 # 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==