View source for HAEM5:Primary large B-cell lymphoma of immune-privileged sites

{{DISPLAYTITLE:Primary large B-cell lymphoma of immune-privileged sites}}

[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

{{Under Construction}}

<blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Diffuse Large B-cell Lymphoma, Not Otherwise Specified]].
Another relevent page is: [[HAEM4:Primary Diffuse Large B-cell Lymphoma of the CNS]]
}}</blockquote>

<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)*==

Ashwini Yenamandra, PhD FACMG, Vanderbilt University Medical Center, Laveniya Satgunaseelan MBBS BMedSc FRCPA, Royal Prince Alfred Hospital
==WHO Classification of Disease==

{| class="wikitable"
!Structure
!Disease
|-
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|Category
|B-cell lymphoid proliferations and lymphomas
|-
|Family
|Mature B-cell neoplasms
|-
|Type
|Large B-cell lymphomas
|-
|Subtype(s)
|Primary large B-cell lymphoma of immune-privileged sites
|}

==Related Terminology==

{| class="wikitable"
|+
|Acceptable
|Primary diffuse large B-cell lymphoma of the CNS; primary diffuse large B-cell lymphoma of the vitreoretina; primary diffuse large B-cell lymphoma of the testis
|-
|Not Recommended
|Primary CNS lymphoma; primary intraocular lymphoma; primary testicular lymphoma
|}

==Gene Rearrangements==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: 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>
{| class="wikitable sortable"
|-
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||''5’BCL6 / 3’IGH''||Overexpression of ''Bcl6'' and impairment of IGH immunoglobulin  due to translocation is thought to be a contributor to CNS-DLNCL pathogenesis<ref name=":42">{{Cite journal|last=Zorofchian|first=Soheil|last2=El-Achi|first2=Hanadi|last3=Yan|first3=Yuanqing|last4=Esquenazi|first4=Yoshua|last5=Ballester|first5=Leomar Y.|date=2018-12|title=Characterization of genomic alterations in primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/30171453|journal=Journal of Neuro-Oncology|volume=140|issue=3|pages=509–517|doi=10.1007/s11060-018-2990-6|issn=1573-7373|pmid=30171453}}</ref>.||t(3;14)(q27;q32)
|17%-20%<ref name=":3">{{Cite journal|last=Chapuy|first=Bjoern|last2=Roemer|first2=Margaretha G. M.|last3=Stewart|first3=Chip|last4=Tan|first4=Yuxiang|last5=Abo|first5=Ryan P.|last6=Zhang|first6=Liye|last7=Dunford|first7=Andrew J.|last8=Meredith|first8=David M.|last9=Thorner|first9=Aaron R.|date=2016-02-18|title=Targetable genetic features of primary testicular and primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/26702065|journal=Blood|volume=127|issue=7|pages=869–881|doi=10.1182/blood-2015-10-673236|issn=1528-0020|pmc=4760091|pmid=26702065}}</ref><ref name=":4">{{Cite journal|last=Zorofchian|first=Soheil|last2=El-Achi|first2=Hanadi|last3=Yan|first3=Yuanqing|last4=Esquenazi|first4=Yoshua|last5=Ballester|first5=Leomar Y.|date=2018-12|title=Characterization of genomic alterations in primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/30171453|journal=Journal of Neuro-Oncology|volume=140|issue=3|pages=509–517|doi=10.1007/s11060-018-2990-6|issn=1573-7373|pmid=30171453}}</ref>
|D, P
|<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''
|''5’IGH / 3’BCL2''
|Uncommon translocation in CNS-DLBCL; can be found in CNS-DLBCL  involving meninges, or secondary involvement by extra-CNS DLBCL<ref name=":43">{{Cite journal|last=Zorofchian|first=Soheil|last2=El-Achi|first2=Hanadi|last3=Yan|first3=Yuanqing|last4=Esquenazi|first4=Yoshua|last5=Ballester|first5=Leomar Y.|date=2018-12|title=Characterization of genomic alterations in primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/30171453|journal=Journal of Neuro-Oncology|volume=140|issue=3|pages=509–517|doi=10.1007/s11060-018-2990-6|issn=1573-7373|pmid=30171453}}</ref>.
|t(14;18)(q31;q21)
|6.7%<ref name=":4" />
|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''
|''5’MYC / 3’IGH''
|Rare translocation in CNS-DLBCL<ref>{{Cite journal|last=Montesinos-Rongen|first=Manuel|last2=Zühlke-Jenisch|first2=Reina|last3=Gesk|first3=Stefan|last4=Martín-Subero|first4=José Ignacio|last5=Schaller|first5=Carlo|last6=Van Roost|first6=Dirk|last7=Wiestler|first7=Otmar D.|last8=Deckert|first8=Martina|last9=Siebert|first9=Reiner|date=2002-10|title=Interphase cytogenetic analysis of lymphoma-associated chromosomal breakpoints in primary diffuse large B-cell lymphomas of the central nervous system|url=https://pubmed.ncbi.nlm.nih.gov/12387458|journal=Journal of Neuropathology and Experimental Neurology|volume=61|issue=10|pages=926–933|doi=10.1093/jnen/61.10.926|issn=0022-3069|pmid=12387458}}</ref>.
|t(8;14)(q24;q32)
|3%<ref>{{Cite journal|last=Cady|first=Francois M.|last2=O'Neill|first2=Brian Patrick|last3=Law|first3=Mark E.|last4=Decker|first4=Paul A.|last5=Kurtz|first5=David M.|last6=Giannini|first6=Caterina|last7=Porter|first7=Alyx B.|last8=Kurtin|first8=Paul J.|last9=Johnston|first9=Patrick B.|date=2008-10-10|title=Del(6)(q22) and BCL6 rearrangements in primary CNS lymphoma are indicators of an aggressive clinical course|url=https://pubmed.ncbi.nlm.nih.gov/18645192|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=26|issue=29|pages=4814–4819|doi=10.1200/JCO.2008.16.1455|issn=1527-7755|pmc=2653136|pmid=18645192}}</ref>
|D
|
|<span class="blue-text">EXAMPLE:</span>

Both balanced and unbalanced forms are observed by FISH (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|''5’ ETV6 / 3’IGH''
|Novel surrogate fusion in CNS-DLBCL indicating favorable prognosis<ref name=":52">{{Cite journal|last=Bruno|first=Aurélie|last2=Labreche|first2=Karim|last3=Daniau|first3=Maïlys|last4=Boisselier|first4=Blandine|last5=Gauchotte|first5=Guillaume|last6=Royer-Perron|first6=Louis|last7=Rahimian|first7=Amithys|last8=Lemoine|first8=Frédéric|last9=de la Grange|first9=Pierre|date=2018-07-05|title=Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29432597|journal=Neuro-Oncology|volume=20|issue=8|pages=1092–1100|doi=10.1093/neuonc/noy019|issn=1523-5866|pmc=6280140|pmid=29432597}}</ref>.
|t(12;14)(p13;q32)
|18%<ref name=":5">{{Cite journal|last=Bruno|first=Aurélie|last2=Labreche|first2=Karim|last3=Daniau|first3=Maïlys|last4=Boisselier|first4=Blandine|last5=Gauchotte|first5=Guillaume|last6=Royer-Perron|first6=Louis|last7=Rahimian|first7=Amithys|last8=Lemoine|first8=Frédéric|last9=de la Grange|first9=Pierre|date=2018-07-05|title=Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29432597|journal=Neuro-Oncology|volume=20|issue=8|pages=1092–1100|doi=10.1093/neuonc/noy019|issn=1523-5866|pmc=6280140|pmid=29432597}}</ref>
|D,P
|
|
|-
|
|''5’PD-L2 / 3’IGL''
|Translocations involving ''PD-L1'' and ''PD-L2'' are  potentially the basis of immune evasion in CNS-DLBCL<ref name=":32">{{Cite journal|last=Chapuy|first=Bjoern|last2=Roemer|first2=Margaretha G. M.|last3=Stewart|first3=Chip|last4=Tan|first4=Yuxiang|last5=Abo|first5=Ryan P.|last6=Zhang|first6=Liye|last7=Dunford|first7=Andrew J.|last8=Meredith|first8=David M.|last9=Thorner|first9=Aaron R.|date=2016-02-18|title=Targetable genetic features of primary testicular and primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/26702065|journal=Blood|volume=127|issue=7|pages=869–881|doi=10.1182/blood-2015-10-673236|issn=1528-0020|pmc=4760091|pmid=26702065}}</ref>.
|t(9;22)(p24;q11)
|13%<ref name=":3" />
|D
|
|
|-
|
|''5’PD-L1 / 3’BCNP1''
|Translocations involving ''PD-L1'' and ''PD-L2'' are  potentially the basis of immune evasion in CNS-DLBCL<ref name=":33">{{Cite journal|last=Chapuy|first=Bjoern|last2=Roemer|first2=Margaretha G. M.|last3=Stewart|first3=Chip|last4=Tan|first4=Yuxiang|last5=Abo|first5=Ryan P.|last6=Zhang|first6=Liye|last7=Dunford|first7=Andrew J.|last8=Meredith|first8=David M.|last9=Thorner|first9=Aaron R.|date=2016-02-18|title=Targetable genetic features of primary testicular and primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/26702065|journal=Blood|volume=127|issue=7|pages=869–881|doi=10.1182/blood-2015-10-673236|issn=1528-0020|pmc=4760091|pmid=26702065}}</ref>.
|t(9;19)(p24;p13)
|13%<ref name=":3" />
|D
|
|
|}


<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}</blockquote>

'''Prognosis:'''  Diagnosis this disease may allow appropriate prophylactic measures, including H1 and H2 blockers, proton pump inhibitors and steroids, to be initiated to minimize its protean complications.


'''Therapeutic Implications:''' 

<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==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>
{| class="wikitable sortable"
|-
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|18
|Gain
|chr18: 45,900,000-61,300,000 [hg38]
|''BCL2''
|
|
|Common recurrent gain (43%) involving ''BCL2''  gene<ref name=":6">{{Cite journal|last=Schwindt|first=H.|last2=Vater|first2=I.|last3=Kreuz|first3=M.|last4=Montesinos-Rongen|first4=M.|last5=Brunn|first5=A.|last6=Richter|first6=J.|last7=Gesk|first7=S.|last8=Ammerpohl|first8=O.|last9=Wiestler|first9=O. D.|date=2009-10|title=Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19494841|journal=Leukemia|volume=23|issue=10|pages=1875–1884|doi=10.1038/leu.2009.120|issn=1476-5551|pmid=19494841}}</ref>.
|-
|19
|Gain
|chr19:55,800,001-58,617,616 [hg38]
|ZNF genes
|
|
|Common recurrent gain (47%) involving ''ZNF''  cluster<ref name=":63">{{Cite journal|last=Schwindt|first=H.|last2=Vater|first2=I.|last3=Kreuz|first3=M.|last4=Montesinos-Rongen|first4=M.|last5=Brunn|first5=A.|last6=Richter|first6=J.|last7=Gesk|first7=S.|last8=Ammerpohl|first8=O.|last9=Wiestler|first9=O. D.|date=2009-10|title=Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19494841|journal=Leukemia|volume=23|issue=10|pages=1875–1884|doi=10.1038/leu.2009.120|issn=1476-5551|pmid=19494841}}</ref>.
|-
|19
|Gain
|chr19:42,900,001-44,700,000 [hg38]
|ZNF genes
|
|
|Recurrent gain (37%) involving ''ZNF''  cluster<ref name=":62">{{Cite journal|last=Schwindt|first=H.|last2=Vater|first2=I.|last3=Kreuz|first3=M.|last4=Montesinos-Rongen|first4=M.|last5=Brunn|first5=A.|last6=Richter|first6=J.|last7=Gesk|first7=S.|last8=Ammerpohl|first8=O.|last9=Wiestler|first9=O. D.|date=2009-10|title=Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19494841|journal=Leukemia|volume=23|issue=10|pages=1875–1884|doi=10.1038/leu.2009.120|issn=1476-5551|pmid=19494841}}</ref>.
|-
|12
|Gain
|chr12: 1-133,275,309  [hg38]
|''STAT6'' and ''CD27''
|
|
|Recurrent gain (26%) involving ''STAT6'' and  ''CD27''<ref name=":64">{{Cite journal|last=Schwindt|first=H.|last2=Vater|first2=I.|last3=Kreuz|first3=M.|last4=Montesinos-Rongen|first4=M.|last5=Brunn|first5=A.|last6=Richter|first6=J.|last7=Gesk|first7=S.|last8=Ammerpohl|first8=O.|last9=Wiestler|first9=O. D.|date=2009-10|title=Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19494841|journal=Leukemia|volume=23|issue=10|pages=1875–1884|doi=10.1038/leu.2009.120|issn=1476-5551|pmid=19494841}}</ref>.
|-
|6
|Loss
|chr6:105,000,001-114,200,000 [hg38]
|''PRDM1''
|
|
|Common recurrent loss (52%) involving ''PRDM1''<ref name=":65">{{Cite journal|last=Schwindt|first=H.|last2=Vater|first2=I.|last3=Kreuz|first3=M.|last4=Montesinos-Rongen|first4=M.|last5=Brunn|first5=A.|last6=Richter|first6=J.|last7=Gesk|first7=S.|last8=Ammerpohl|first8=O.|last9=Wiestler|first9=O. D.|date=2009-10|title=Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19494841|journal=Leukemia|volume=23|issue=10|pages=1875–1884|doi=10.1038/leu.2009.120|issn=1476-5551|pmid=19494841}}</ref>.
|-
|6
|Loss
|chr6:32,100,001-33,500,000 [hg38]
|MHC genes
|
|
|Loss affecting 74% of CNS-DLBCL cases overall,  with region harboring MHC genes including ''HLA-DRB, HLA-DQA and HLA-DQB (''37%  homozygous deletion and 37% uniparental disomy)<ref name=":66">{{Cite journal|last=Schwindt|first=H.|last2=Vater|first2=I.|last3=Kreuz|first3=M.|last4=Montesinos-Rongen|first4=M.|last5=Brunn|first5=A.|last6=Richter|first6=J.|last7=Gesk|first7=S.|last8=Ammerpohl|first8=O.|last9=Wiestler|first9=O. D.|date=2009-10|title=Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19494841|journal=Leukemia|volume=23|issue=10|pages=1875–1884|doi=10.1038/leu.2009.120|issn=1476-5551|pmid=19494841}}</ref>.
|-
|8
|Loss
|chr8:54,600,001-60,600,001 [hg38]
|''TOX,  CA8'' and ''RAB2A''
|
|
|Common recurrent loss (32%) involving ''TOX,  CA8'' and ''RAB2A''<ref name=":67">{{Cite journal|last=Schwindt|first=H.|last2=Vater|first2=I.|last3=Kreuz|first3=M.|last4=Montesinos-Rongen|first4=M.|last5=Brunn|first5=A.|last6=Richter|first6=J.|last7=Gesk|first7=S.|last8=Ammerpohl|first8=O.|last9=Wiestler|first9=O. D.|date=2009-10|title=Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19494841|journal=Leukemia|volume=23|issue=10|pages=1875–1884|doi=10.1038/leu.2009.120|issn=1476-5551|pmid=19494841}}</ref>.
|-
|9
|Loss
|chr9:19,900,001-25,600,000 [hg38]
|''CDKN2A/B''
|
|
|Common recurrent loss (48%) involving ''CDKN2A/B''  (32% homozygous deletion; 16% partial uniparental disomy)<ref name=":68">{{Cite journal|last=Schwindt|first=H.|last2=Vater|first2=I.|last3=Kreuz|first3=M.|last4=Montesinos-Rongen|first4=M.|last5=Brunn|first5=A.|last6=Richter|first6=J.|last7=Gesk|first7=S.|last8=Ammerpohl|first8=O.|last9=Wiestler|first9=O. D.|date=2009-10|title=Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19494841|journal=Leukemia|volume=23|issue=10|pages=1875–1884|doi=10.1038/leu.2009.120|issn=1476-5551|pmid=19494841}}</ref>.
|}

<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>

'''AMPLIFICATION''': BCL2, REL, CD274, PDCD1LG2, JAK2, KRAs, TBL1XR1, RB1

'''DELETION''': CDKN2A, TNFAIP3, CDKN2B, TNFRSF14, CD70, CD58, PTEN
{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|<span class="blue-text">EXAMPLE:</span> 8||<span class="blue-text">EXAMPLE:</span> Gain||<span class="blue-text">EXAMPLE:</span> chr8:0-1000000
|-
|<span class="blue-text">EXAMPLE:</span> 7||<span class="blue-text">EXAMPLE:</span> Loss||<span class="blue-text">EXAMPLE:</span> chr7:0-1000000
|}	
		
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==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>
{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Molecular Pathogenesis
!Prevalence - 
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
|<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).
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|-
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated 
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|
|
|
|
|
|
|}

<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>

Due to the clinicopathologic, biological and genetic diversity, DLBCL is sub divided into morphological variants and molecular subtypes. Initial workup and evaluation of DLBCL has become increasingly complex partly due to the genetic abnormalities that are targets for specific therapy and play an important role in monitoring residual disease. Genomic studies help in clinical management, risk stratification, enrolling patients onto treatment protocols, clinical trials, and detection of therapeutic targets. GS, If IHC is positive for GCB like DLBCL, FISH and Cytogenetics for MYC, BCL2 or BCL6 gene rearrangement are recommended to rule out double and triple hit lymphoma. 

<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
|-
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|''MYD88;''
GOF mutation
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Oncogene
|50% to 76%<ref>{{Cite journal|last=Montesinos-Rongen|first=Manuel|last2=Godlewska|first2=Elzbieta|last3=Brunn|first3=Anna|last4=Wiestler|first4=Otmar D.|last5=Siebert|first5=Reiner|last6=Deckert|first6=Martina|date=2011-12|title=Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/22020631|journal=Acta Neuropathologica|volume=122|issue=6|pages=791–792|doi=10.1007/s00401-011-0891-2|issn=1432-0533|pmid=22020631}}</ref><ref name=":7">{{Cite journal|last=Nakamura|first=T.|last2=Tateishi|first2=K.|last3=Niwa|first3=T.|last4=Matsushita|first4=Y.|last5=Tamura|first5=K.|last6=Kinoshita|first6=M.|last7=Tanaka|first7=K.|last8=Fukushima|first8=S.|last9=Takami|first9=H.|date=2016-04|title=Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/26111727|journal=Neuropathology and Applied Neurobiology|volume=42|issue=3|pages=279–290|doi=10.1111/nan.12259|issn=1365-2990|pmid=26111727}}</ref>
|D
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|Common missense mutation is ''MYD88''  L265P. Affects NF-kB pathway synergistically with ''CARD11'' (occurring in  29%<ref name=":34">{{Cite journal|last=Chapuy|first=Bjoern|last2=Roemer|first2=Margaretha G. M.|last3=Stewart|first3=Chip|last4=Tan|first4=Yuxiang|last5=Abo|first5=Ryan P.|last6=Zhang|first6=Liye|last7=Dunford|first7=Andrew J.|last8=Meredith|first8=David M.|last9=Thorner|first9=Aaron R.|date=2016-02-18|title=Targetable genetic features of primary testicular and primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/26702065|journal=Blood|volume=127|issue=7|pages=869–881|doi=10.1182/blood-2015-10-673236|issn=1528-0020|pmc=4760091|pmid=26702065}}</ref>).
|-
|''CD79B;'' GOF mutation
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Oncogene
|83%<ref name=":7" />
|D
|
|Both ''CD79B'' and ''MYD88'' lead  to constitutive action of NF-kB pathway<ref name=":72">{{Cite journal|last=Nakamura|first=T.|last2=Tateishi|first2=K.|last3=Niwa|first3=T.|last4=Matsushita|first4=Y.|last5=Tamura|first5=K.|last6=Kinoshita|first6=M.|last7=Tanaka|first7=K.|last8=Fukushima|first8=S.|last9=Takami|first9=H.|date=2016-04|title=Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/26111727|journal=Neuropathology and Applied Neurobiology|volume=42|issue=3|pages=279–290|doi=10.1111/nan.12259|issn=1365-2990|pmid=26111727}}</ref>.
|-
|''SHIP;''
Loss of function 
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Tumor suppressor gene
|25%<ref name=":8">{{Cite journal|last=Deckert|first=Martina|last2=Montesinos-Rongen|first2=Manuel|last3=Brunn|first3=Anna|last4=Siebert|first4=Reiner|date=2014-02|title=Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice|url=https://pubmed.ncbi.nlm.nih.gov/24240734|journal=Acta Neuropathologica|volume=127|issue=2|pages=175–188|doi=10.1007/s00401-013-1202-x|issn=1432-0533|pmid=24240734}}</ref>
|
|
|Component of B-cell receptor signaling  cascade altered by point mutation in ''SHIP''<ref name=":82">{{Cite journal|last=Deckert|first=Martina|last2=Montesinos-Rongen|first2=Manuel|last3=Brunn|first3=Anna|last4=Siebert|first4=Reiner|date=2014-02|title=Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice|url=https://pubmed.ncbi.nlm.nih.gov/24240734|journal=Acta Neuropathologica|volume=127|issue=2|pages=175–188|doi=10.1007/s00401-013-1202-x|issn=1432-0533|pmid=24240734}}</ref>.
|-
|
|
|
|
|
|
|
|}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.

<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>

'''SNV''' : MLL2, TP53, MYD88, B2M, CREBBP, TNFAIP3, PIM1, BCL2, EZH2, TNFRSF14, CD79B

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|<span class="blue-text">EXAMPLE:</span> TP53||<span class="blue-text">EXAMPLE:</span> R273H||<span class="blue-text">EXAMPLE:</span> Tumor Suppressor||<span class="blue-text">EXAMPLE:</span> LOF||<span class="blue-text">EXAMPLE:</span> 20%
|}	
		
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|-
|Secondary Mutations||<span class="blue-text">EXAMPLE:</span> Trisomy 7
|-
|Mutually Exclusive||<span class="blue-text">EXAMPLE:</span> EGFR Amplification
|}

<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Epigenomic Alterations==

Promoter hypermethylation of genes has been established as a potential pathogenetic mechanism in CNS-DLBCL<ref name=":9">{{Cite journal|last=Chu|first=Linda C.|last2=Eberhart|first2=Charles G.|last3=Grossman|first3=Stuart A.|last4=Herman|first4=James G.|date=2006-11-15|title=Epigenetic silencing of multiple genes in primary CNS lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/16858686|journal=International Journal of Cancer|volume=119|issue=10|pages=2487–2491|doi=10.1002/ijc.22124|issn=0020-7136|pmid=16858686}}</ref>. Genes affected include ''DAPK'' (84% of CNS-DLBCL cases), ''CDKN2A/B'' (75%), ''TSP1'' (68%), ''MGMT'' (52%) and ''RFC'' (30%)<ref name=":9" /><ref>{{Cite journal|last=Ferreri|first=Andrés J. M.|last2=Dell'Oro|first2=Stefania|last3=Capello|first3=Daniela|last4=Ponzoni|first4=Maurilio|last5=Iuzzolino|first5=Paolo|last6=Rossi|first6=Davide|last7=Pasini|first7=Felice|last8=Ambrosetti|first8=Achille|last9=Orvieto|first9=Enrico|date=2004-09|title=Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/15327516|journal=British Journal of Haematology|volume=126|issue=5|pages=657–664|doi=10.1111/j.1365-2141.2004.05109.x|issn=0007-1048|pmid=15327516}}</ref>). ''RFC'' promoter hypermethylation may have a theranostic role in those treated with high-dose methotrexate regimens.

==Genes and Main Pathways Involved==


Genetic alterations observed in CNS-DLBCL converge on the NF-kB pathway, leading to its constitutive activation. The gene pathways upstream of the NF-kB complex are affected in CNS-DLBCL. These include the B-cell receptor pathway (''SHIP'', ''CD79B''), its target pathway, the BCM complex (''CARD11, MALT1'') and toll-like receptor pathway (''MYD88'')<ref name=":83">{{Cite journal|last=Deckert|first=Martina|last2=Montesinos-Rongen|first2=Manuel|last3=Brunn|first3=Anna|last4=Siebert|first4=Reiner|date=2014-02|title=Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice|url=https://pubmed.ncbi.nlm.nih.gov/24240734|journal=Acta Neuropathologica|volume=127|issue=2|pages=175–188|doi=10.1007/s00401-013-1202-x|issn=1432-0533|pmid=24240734}}</ref><ref>{{Cite journal|last=Vater|first=I.|last2=Montesinos-Rongen|first2=M.|last3=Schlesner|first3=M.|last4=Haake|first4=A.|last5=Purschke|first5=F.|last6=Sprute|first6=R.|last7=Mettenmeyer|first7=N.|last8=Nazzal|first8=I.|last9=Nagel|first9=I.|date=2015-03|title=The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing|url=https://pubmed.ncbi.nlm.nih.gov/25189415|journal=Leukemia|volume=29|issue=3|pages=677–685|doi=10.1038/leu.2014.264|issn=1476-5551|pmid=25189415}}</ref>.

<span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<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
|-
|
|
|
|}

<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>

B-Cell differentiation, TP53 pathway, NF-kB pathway, Apoptosis, Cell migration, Immune response,BCR-MYD88 signaling, PI3K-AKT-mTCR pathway

<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Genetic Diagnostic Testing Methods==

NGS, If IHC is positive for GCB like DLBCL, FISH and Cytogenetics for MYC, BCL2 or BCL6 gene rearrangement are recommended to rule out double and triple hit lymphoma.Diagnostic testing methods include karyotyping, fluorescent ''in situ'' hybridization, RT-PCR and next generation sequencing techniques (whole genome/whole exome sequencing).

==Familial Forms==

Not applicable

==Additional Information==

Not applicable

==Links==


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==References==
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<br />

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):  

        
<nowiki>*</nowiki>''Citation of this Page'': “Primary large B-cell lymphoma of immune-privileged sites”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Primary_large_B-cell_lymphoma_of_immune-privileged_sites</nowiki>.
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases P]]