Compendium of Cancer Genome Aberrations

HAEM5:Classic Hodgkin lymphoma: Difference between revisions

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No characteristic chromosomal rearrangements have been reported for lymphocyte-rich classical Hodgkin's lymphoma.


==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>
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>
Recurrent chromosomal imbalances are characteristic of CHL and contribute to its pathogenesis. Frequent gains include 2p (''REL''), 9p24.1 (''JAK2'', ''CD274/PDL1'', ''PDCD1LG2/PDL2''), and 17q21 (''MAP3K14''), while recurrent losses include 6q23–q24 (''TNFAIP3''). These alterations support activation of NF-κB and JAK/STAT pathways, as well as immune evasion.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 80: Line 80:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|2p
7
|gain
|<span class="blue-text">EXAMPLE:</span> Loss
|2p13
|<span class="blue-text">EXAMPLE:</span>
|''REL''
chr7
|P
|<span class="blue-text">EXAMPLE:</span>
|No
Unknown
|REL amplification promotes NF-κB signaling activation that promotes HRS cell survival and proliferation.<ref>{{Cite journal|last=Joos|first=Stefan|last2=Menz|first2=Christiane K.|last3=Wrobel|first3=Gunnar|last4=Siebert|first4=Reiner|last5=Gesk|first5=Stefan|last6=Ohl|first6=Sibylle|last7=Mechtersheimer|first7=Gunhild|last8=Trümper|first8=Lorenz|last9=Möller|first9=Peter|date=2002-02-15|title=Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2|url=https://pubmed.ncbi.nlm.nih.gov/11830490|journal=Blood|volume=99|issue=4|pages=1381–1387|doi=10.1182/blood.v99.4.1381|issn=0006-4971|pmid=11830490}}</ref><ref>{{Cite journal|last=Martín-Subero|first=José I.|last2=Gesk|first2=Stefan|last3=Harder|first3=Lana|last4=Sonoki|first4=Takashi|last5=Tucker|first5=Philip W.|last6=Schlegelberger|first6=Brigitte|last7=Grote|first7=Werner|last8=Novo|first8=Francisco J.|last9=Calasanz|first9=María J.|date=2002-02-15|title=Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/11830502|journal=Blood|volume=99|issue=4|pages=1474–1477|doi=10.1182/blood.v99.4.1474|issn=0006-4971|pmid=11830502}}</ref><ref name=":2">{{Cite journal|last=Steidl|first=Christian|last2=Telenius|first2=Adele|last3=Shah|first3=Sohrab P.|last4=Farinha|first4=Pedro|last5=Barclay|first5=Lorena|last6=Boyle|first6=Merrill|last7=Connors|first7=Joseph M.|last8=Horsman|first8=Douglas E.|last9=Gascoyne|first9=Randy D.|date=2010-07-22|title=Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome|url=https://pubmed.ncbi.nlm.nih.gov/20339089|journal=Blood|volume=116|issue=3|pages=418–427|doi=10.1182/blood-2009-12-257345|issn=1528-0020|pmid=20339089}}</ref>
|<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>
|9p
8
|Gain
|<span class="blue-text">EXAMPLE:</span> Gain
|9p24.1
|<span class="blue-text">EXAMPLE:</span>
|''CD274'' (PD-L1), ''PDCD1LG2'' (PD-L2), JAK2
chr8
|T, P
|<span class="blue-text">EXAMPLE:</span>
|Yes <ref name=":1" />
Unknown
|9p24.1 amplification drives PD-L1/PD-L2 overexpression leading to immune suppression. Relevant for immune checkpoint inhibitor therapy <ref name=":1">{{Cite journal|last=Green|first=Michael R.|last2=Monti|first2=Stefano|last3=Rodig|first3=Scott J.|last4=Juszczynski|first4=Przemyslaw|last5=Currie|first5=Treeve|last6=O'Donnell|first6=Evan|last7=Chapuy|first7=Bjoern|last8=Takeyama|first8=Kunihiko|last9=Neuberg|first9=Donna|date=2010-10-28|title=Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/20628145|journal=Blood|volume=116|issue=17|pages=3268–3277|doi=10.1182/blood-2010-05-282780|issn=1528-0020|pmc=2995356|pmid=20628145}}</ref><ref>{{Cite journal|last=Roemer|first=Margaretha G. M.|last2=Advani|first2=Ranjana H.|last3=Ligon|first3=Azra H.|last4=Natkunam|first4=Yasodha|last5=Redd|first5=Robert A.|last6=Homer|first6=Heather|last7=Connelly|first7=Courtney F.|last8=Sun|first8=Heather H.|last9=Daadi|first9=Sarah E.|date=2016-08-10|title=PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC5019753/|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=34|issue=23|pages=2690–2697|doi=10.1200/JCO.2016.66.4482|issn=1527-7755|pmc=5019753|pmid=27069084}}</ref>
|<span class="blue-text">EXAMPLE:</span> D, P
|-
|
|17q
|<span class="blue-text">EXAMPLE:</span>
|Gain
Common recurrent secondary finding for t(8;21) (add references).
|17q21
|''MAP3K14''
|P
|No
|MAP3K14 (NIK) gain activates alternative NF-κB signaling <ref name=":2" />
|-
|19q
|Gain
|19q13.3
|''RELB''
|P
|No
|Overexpression of RELB leads to enhanced NF-kB signaling and HRS cell survival. <ref>{{Cite journal|last=Slovak|first=Marilyn L.|last2=Bedell|first2=Victoria|last3=Hsu|first3=Ya-Hsuan|last4=Estrine|first4=Dolores B.|last5=Nowak|first5=Norma J.|last6=Delioukina|first6=Maria L.|last7=Weiss|first7=Lawrence M.|last8=Smith|first8=David D.|last9=Forman|first9=Stephen J.|date=2011-05-15|title=Molecular karyotypes of Hodgkin and Reed-Sternberg cells at disease onset reveal distinct copy number alterations in chemosensitive versus refractory Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/21385932|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=17|issue=10|pages=3443–3454|doi=10.1158/1078-0432.CCR-10-1071|issn=1557-3265|pmc=3096736|pmid=21385932}}</ref>
|-
|20q
|Gain
|20q13
|''CD40''
|P
|No
|Over expression of CD40 activates NF-kB signaling, promotes proliferation and immune evasion.<ref>{{Cite journal|last=Alibrahim|first=Mohamed N.|last2=Gloghini|first2=Annunziata|last3=Carbone|first3=Antonino|date=2024-12-05|title=Pathobiological Features and Therapeutic Opportunities Linked to TNF Family Member Expression in Classic Hodgkin Lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/39682256|journal=Cancers|volume=16|issue=23|pages=4070|doi=10.3390/cancers16234070|issn=2072-6694|pmc=11640334|pmid=39682256}}</ref><ref>{{Cite journal|last=De Re|first=Valli|last2=Caggiari|first2=Laura|last3=Repetto|first3=Ombretta|last4=Mussolin|first4=Lara|last5=Mascarin|first5=Maurizio|date=2019-10-02|title=Classical Hodgkin's Lymphoma in the Era of Immune Checkpoint Inhibition|url=https://pubmed.ncbi.nlm.nih.gov/31581738|journal=Journal of Clinical Medicine|volume=8|issue=10|pages=1596|doi=10.3390/jcm8101596|issn=2077-0383|pmc=6832444|pmid=31581738}}</ref>
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|6q
17
|Loss
|<span class="blue-text">EXAMPLE:</span> Amp
|6q23-24
|<span class="blue-text">EXAMPLE:</span>
|''TNFAIP3''
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|P
|<span class="blue-text">EXAMPLE:</span>
|No
''ERBB2''
|Loss of TNFAIP3 (A20), a negative regulator of NF‑κB,  enhance NF-kB signling <ref name=":0">{{Cite journal|last=Schmitz|first=Roland|last2=Hansmann|first2=Martin-Leo|last3=Bohle|first3=Verena|last4=Martin-Subero|first4=Jose Ignacio|last5=Hartmann|first5=Sylvia|last6=Mechtersheimer|first6=Gunhild|last7=Klapper|first7=Wolfram|last8=Vater|first8=Inga|last9=Giefing|first9=Maciej|date=2009-05-11|title=TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19380639|journal=The Journal of Experimental Medicine|volume=206|issue=5|pages=981–989|doi=10.1084/jem.20090528|issn=1540-9538|pmc=2715030|pmid=19380639}}</ref>
|<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.
|-
|-
|
|13q
|
|Loss
|
|13q14
|
|''RB1''
|
|P
|
|No
|
|loss of tumor suppressors and contribute to HRS cell survival
|}
|}


There is no typical findings for lymphocyte-rich classical Hodgkin's lymphoma, the main features are also seen in other classical Hodgkin's lymphoma subtypes.
The table below seems duplicated, can be deleted?


{| 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>
|Aneuploidy
Co-deletion of 1p and 18q
|Chromosomal instability
|<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
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|P
|<span class="blue-text">EXAMPLE:</span> D, P
|No
|
|Common in HRS cells; associated with genomic instability and disease progression (PMID: 7632954)
|
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Hypertetraploidy
Microsatellite instability - hypermutated
|Chromosomal duplication leading to genome-wide imbalance
|
|Recurrent (5–20%)
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|P
|<span class="blue-text">EXAMPLE:</span> P, T
|No
|
|Frequently observed in CHL; reflects chromosomal instability (PMID: 7632954)
|
|-
|-
|
|Recurrent chromosomal imbalances (e.g., 2p, 9p, 17q gains; 6q loss)
|
|Deregulated NF-κB and JAK/STAT signaling; immune evasion
|
|Common (>20%)
|
|P,T
|
|Yes (PMID: 19380639, 20628145)
|
|Involves REL, JAK2, PD-L1, PD-L2, TNFAIP3; contributes to pathogenesis and guides immunotherapy potential
|}
|}


No characteristic chromosomal patterns have been reported for lymphocyte-rich classical Hodgkin's lymphoma.
The below table can be deleted?


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Notes
!Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Aneuploidy, hypertetraploidy
 
Co-deletion of 1p and 18q
|Yes
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>
|unkonwn
 
|unknown
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|Common in HRS cells; contributes to genomic instability (PMID: 7632954)
|}
|}


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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|TNFAIP3
 
|Inactivating mutation
<br />
|Tumor Suppressor Gene
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Recurrent (5-20%)
|<span class="blue-text">EXAMPLE:</span> Oncogene
|P
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|No
|<span class="blue-text">EXAMPLE:</span> T
|Loss of function mutations disrupt NF-κB regulation (PMID: 19380639)
|<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
|Frameshift and nonsense mutations
|Tumor Suppressor Gene
|Recurrent (5-20%)
|P
|No
|SOCS1 mutations activate JAK/STAT signaling (PMID: 24531327)
|-
|STAT6
|Missense mutations
|Oncogene
|Recurrent (5-20%)
|P
|No
|STAT6 mutations drive cytokine signaling alterations (PMID: 24531327, 29650799)
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|B2M
<br />
|Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Tumor Suppressor Gene
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Rare (<5%)
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|P
|<span class="blue-text">EXAMPLE:</span> P
|No
|
|Loss of MHC class I expression aids immune evasion (PMID: 21368758)
|<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.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|CIITA
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Tumor Suppressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Rare (<5%)
|<span class="blue-text">EXAMPLE:</span> T
|P
|
|No
|
|Loss of MHC class II expression aids immune evasion (PMID: 21368758)
|-
|-
|
|XPO1
|
|Missense mutations
|
|Oncogene
|
|Rare (<5%)
|
|Unknown
|
|No
|
|Emerging evidence of role in CHL pathogenesis (PMID: 33686198)
|}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.


Line 335: Line 354:
==Epigenomic Alterations==
==Epigenomic Alterations==


N/A
Global downregulation of B-cell transcription factors (OCT2, BOB1, PU.1) and epigenetic silencing of B-cell program genes (PMID: 19465900, 14694522)


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
N/A
{| 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
|REL, TNFAIP3, NFKBIA, MAP3K14
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|NF-κB signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Constitutive activation of classical and alternative NF-κB pathways promotes HRS cell survival (PMID: 19380639, 33686198)
|-
|JAK2, STAT6, SOCS1
|JAK/STAT signaling
|Dysregulation leads to proliferation and survival of HRS cells (PMID: 24531327, 29650799)
|-
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|CD274 (PD-L1), PDCD1LG2 (PD-L2), B2M
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|Immune evasion
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Upregulation of PD-L1/PD-L2 and loss of MHC I/II expression enables immune escape (PMID: 20628145, 21368758)
|-
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|EBV LMP1, LMP2A
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|Viral oncogenesis
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
|LMP1 mimics CD40 signaling, LMP2A mimics BCR signaling to promote HRS cell survival in EBV+ CHL (PMID: 9501091, 17682125)
|-
|-
|''REL'' (2p16), ''RELB'' (19q13), ''CD40'' (20q13) and ''MAP3K14'' (17q21)
|nuclear factor (NF)-κB signalling
|
|
|-
|
|''JAK2'' amplification
|PD-L1 protein expression/ JAK/STAT pathway
|
|
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


N/A
*Immunohistochemistry for CD30, CD15, PAX5, and EBV (EBER in situ hybridization) (PMID: 2477085, 6946981)
*9p24.1 copy number assessment (FISH or NGS) may be used in refractory/relapsed cases to evaluate PD-L1/PD-L2 amplification for potential immunotherapy (PMID: 29394125).
*TR clonality assays can help exclude T-cell lymphomas in challenging differential diagnoses (PMID: 24128129).
*Targeted NGS panels for NF-κB and JAK/STAT pathway mutations (PMID: 33686198)


==Familial Forms==
==Familial Forms==


N/A
Familial aggregation and monozygotic twin concordance suggest genetic predisposition (PMID: 26311361, 34208754)


==Additional Information==
==Additional Information==
Retrieved from "https://test.ccga.io/index.php/HAEM5:Classic_Hodgkin_lymphoma"