Compendium of Cancer Genome Aberrations

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

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==Gene Rearrangements==
==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>{{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>{{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" />
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"
{| class="wikitable sortable"
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!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|<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). BCR::ABL1 is generally favorable in CML (add reference).
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
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==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
None reported so far.
 
{| class="wikitable sortable"
{| class="wikitable sortable"
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!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
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 references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
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==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
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"
{| class="wikitable sortable"
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|6q deletions<ref name=":2" />
Co-deletion of 1p and 18q
|Tumor-suppressor genes: ''PRDM1 and A20''<ref name=":2" />
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|Common<ref name=":2" />
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|D
|<span class="blue-text">EXAMPLE:</span> D, P
|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>
|
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|6p25.3 amplifications<ref name=":1" />
Microsatellite instability - hypermutated
|5 different genes including the oncogene ''IRF4'' are located<ref name=":1" />
|
|Common<ref name=":1" />
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|May be D
|<span class="blue-text">EXAMPLE:</span> P, T
|No
|
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|-
|-
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|9p24.1 amplifications<ref name=":1" />
|
|''PD-L1/PD-L2'' and ''JAK2''<ref name=":1" />
|
|Recurrent<ref name=":1" />
|
|May be T
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|No
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|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)==
==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>
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"
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''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 />
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Loss of function aberration in the SH2 domain<ref name=":1" />
|<span class="blue-text">EXAMPLE:</span> Oncogene
|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>
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Common<ref name=":1" /><ref name=":2" /><ref name=":3" />
|<span class="blue-text">EXAMPLE:</span> T
|P, T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|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>
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|''STAT3''<ref name=":1" /><ref name=":2" />
<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Activating missense mutations<ref name=":1" />  
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|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>
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|Common<ref name=":1" /><ref name=":2" />
|<span class="blue-text">EXAMPLE:</span> P
|T
|
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|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> ''BRAF''; Activating mutations
|''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>
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|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> Common (melanoma)
|Common<ref name=":1" /><ref name=":2" /><ref name=":5" />
|<span class="blue-text">EXAMPLE:</span> T
|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.
|}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==
Put your text here
None identified so far.
==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: Please include references throughout the table. Do not delete the table.)''</span>
Line 244: Line 193:
!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>
|-
|-
|<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
|-
|-
|
|
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# 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>
# 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  
# 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==
==Notes==
Retrieved from "https://test.ccga.io/index.php/HAEM5:EBV-positive_diffuse_large_B-cell_lymphoma"