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HAEM5:Diffuse large B-cell lymphoma / high grade B-cell lymphoma with MYC and BCL2 rearrangements (view source)

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{{DISPLAYTITLE:Diffuse large B-cell lymphoma / high grade B-cell lymphoma with MYC and BCL2 rearrangements}}

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

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

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}}</blockquote>

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(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ HUGO-approved gene names and symbols] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples)~~; to add (or move) a row or column to a table, click nearby within the table and select the > symbol that appears to be given options~~. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see [[Author_Instructions]] and [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [mailto:CCGA@cancergenomics.org Technical Support])

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(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ HUGO-approved gene names and symbols] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). 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 [[Author_Instructions]] and [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [mailto:CCGA@cancergenomics.org Technical Support])

==Primary Author(s)*==

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==Definition / Description of Disease==

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Put your text here (''Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories, diagnostic criteria if applicable, and differential diagnosis if applicable~~. Other classifications can be referenced for comparison.~~'')

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Put your text here (''Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories referring to the specific WHO book pages, diagnostic criteria if applicable, and differential diagnosis if applicable'')

==Synonyms / Terminology==

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==Clinical Features==

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Put your text here and fill in the table (''Instruction: Can include references in the table~~. Do not delete table.~~'')

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Put your text here and fill in the table (''Instruction: Can include references in the table'')

{| class="wikitable"

|'''Signs and Symptoms'''

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|~~~~EXAMPLE~~:~~ Asymptomatic (incidental finding on complete blood counts)

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|EXAMPLE Asymptomatic (incidental finding on complete blood counts)

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~~~~EXAMPLE~~:~~ B-symptoms (weight loss, fever, night sweats)

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EXAMPLE B-symptoms (weight loss, fever, night sweats)

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~~~~EXAMPLE~~:~~ Fatigue

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EXAMPLE Fatigue

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~~~~EXAMPLE~~:~~ Lymphadenopathy (uncommon)

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EXAMPLE Lymphadenopathy (uncommon)

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|'''Laboratory Findings'''

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|~~~~EXAMPLE~~:~~ Cytopenias

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|EXAMPLE Cytopenias

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~~~~EXAMPLE~~:~~ Lymphocytosis (low level)

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EXAMPLE Lymphocytosis (low level)

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<blockquote class='blockedit'>{{Box-round|title=~~HAEM5 Conversion Notes~~|~~Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification~~}}

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<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}

Patients typically show Ann Arbor stage IV disease at diagnosis<ref name=":20" /> with involvement of more than one extra-nodal site and a high International Prognostic Index (IPI) score<ref name=":0" /><ref name=":1" /><ref name=":5">{{Cite journal|last=Xia|first=Yang|last2=Zhang|first2=Xinlian|date=2020|title=The Spectrum of MYC Alterations in Diffuse Large B-Cell Lymphoma|url=https://www.karger.com/Article/FullText/505892|journal=Acta Haematologica|language=en|volume=143|issue=6|pages=520–528|doi=10.1159/000505892|issn=0001-5792}}</ref>. B symptoms (fever, night sweats and weight loss) are common at diagnosis, as is poor performance status<ref name=":1" /><ref name=":3" /><ref name=":5" />. Patients almost invariably show elevated serum lactate dehydrogenase and, less frequently, leucocytosis<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" />.

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!Notes

|-

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|~~~~EXAMPLE~~:~~ t(9;22)(q34;q11.2)||~~~~EXAMPLE~~:~~ 3'ABL1 / 5'BCR||~~~~EXAMPLE~~:~~ der(22)||~~~~EXAMPLE~~:~~ 20% (COSMIC)

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|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)

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~~~~EXAMPLE~~:~~ 30% (add reference)

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EXAMPLE 30% (add reference)

|Yes

|No

|Yes

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

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).

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<blockquote class='blockedit'>{{Box-round|title=~~HAEM5 Conversion Notes~~|~~Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification~~}}

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<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}

This subtype of B-cell lymphoma is defined by a rearrangement of the MYC proto-oncogene, located on chromosome 8q24. In 39-65% of cases the translocation partner is an immunoglobulin gene, most commonly the IGH region on chromosome 14q32 with the IGK (2p12) and IGL (22q11.2) gene loci less frequently involved<ref name=":0" /><ref name=":7" /><ref name=":2" /><ref name=":8" /><ref name=":4" /><ref>{{Cite journal|last=Pedersen|first=Mette Ø.|last2=Gang|first2=Anne O.|last3=Poulsen|first3=Tim S.|last4=Knudsen|first4=Helle|last5=Lauritzen|first5=Anne F.|last6=Nielsen|first6=Signe L.|last7=Klausen|first7=Tobias W.|last8=Nørgaard|first8=Peter|date=2014-01|title=MYC translocation partner gene determines survival of patients with large B-cell lymphoma with MYC- or double-hit MYC/BCL2 translocations|url=https://onlinelibrary.wiley.com/doi/10.1111/ejh.12212|journal=European Journal of Haematology|language=en|volume=92|issue=1|pages=42–48|doi=10.1111/ejh.12212}}</ref>. Non-IG gene partners include 9p13 and 3q27.3 (BCL6)<ref name=":8" />. Additionally, all cases must harbour a BCL2 (18q21.3) and/or BCL6 (3q27.3) rearrangement.

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<blockquote class='blockedit'>{{Box-round|title=~~HAEM5 Conversion Notes~~|Please incorporate this section into the relevant tables found in:

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<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

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==Individual Region Genomic Gain / Loss / LOH==

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Put your text here and fill in the table (''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable~~. Do not delete table~~.'')

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Put your text here and fill in the table (''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'')

{| class="wikitable sortable"

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!Notes

|-

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

7

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|~~~~EXAMPLE~~:~~ Loss

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|EXAMPLE Loss

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

chr7:1- 159,335,973 [hg38]

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

chr7

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|Yes

|No

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

8

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|~~~~EXAMPLE~~:~~ Gain

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|EXAMPLE Gain

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

chr8:1-145,138,636 [hg38]

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

chr8

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|No

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

Common recurrent secondary finding for t(8;21) (add reference).

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<blockquote class='blockedit'>{{Box-round|title=~~HAEM5 Conversion Notes~~|~~Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification~~}}

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

High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements almost invariably display a complex karyotype with many cytogenetic abnormalities<ref name=":0" /><ref name=":2" /><ref name=":4" />. Gains of chromosomes 8q and 12q are more common in HGBL-DH/TH than in cases with isolated MYC translocation<ref name=":8" />. 12q12-q15 copy-number gain is significantly more common in HGBL with MYC and BCL2 translocation than in cases with BCL6 translocation<ref name=":4" />.

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==Characteristic Chromosomal Patterns==

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Put your text here (''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis~~. Do not delete table.~~'')

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Put your text here (''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')

{| class="wikitable sortable"

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!Notes

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|~~~~EXAMPLE~~:~~

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|EXAMPLE

Co-deletion of 1p and 18q

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|No

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|~~~~EXAMPLE:~~~~

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|EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

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==Gene Mutations (SNV / INDEL)==

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Put your text here and fill in the table (''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity~~. Do not delete table~~.'')

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Put your text here and fill in the table (''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'')

{| class="wikitable sortable"

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!Notes

|-

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|~~~~EXAMPLE:~~~~ TP53; Variable LOF mutations

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|EXAMPLE: TP53; Variable LOF mutations

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~~~~EXAMPLE:~~~~

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EXAMPLE:

EGFR; Exon 20 mutations

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~~~~EXAMPLE:~~~~ BRAF; Activating mutations

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EXAMPLE: BRAF; Activating mutations

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|~~~~EXAMPLE:~~~~ TSG

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|EXAMPLE: TSG

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|~~~~EXAMPLE:~~~~ 20% (COSMIC)

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|EXAMPLE: 20% (COSMIC)

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~~~~EXAMPLE:~~~~ 30% (add Reference)

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EXAMPLE: 30% (add Reference)

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|~~~~EXAMPLE:~~~~ IDH1 R123H

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|EXAMPLE: IDH1 R123H

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|~~~~EXAMPLE:~~~~ EGFR amplification

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|EXAMPLE: EGFR amplification

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|~~~~EXAMPLE:~~~~ Excludes hairy cell leukemia (HCL) (add reference).

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|EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).

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<blockquote class='blockedit'>{{Box-round|title=~~HAEM5 Conversion Notes~~|~~Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification~~}}

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

Due to the relatively recent classification of HGBL with MYC and BCL2 and/or BCL6 translocation as a specific pathological entity, combined with small sample sizes, comprehensive data on gene mutation prevalence is not currently available. However, several studies have shown the mutational profile of HGBL DH/TH to differ significantly from that of DLBCL, NOS. Frequently mutations are associated with apoptosis and cell cycle pathways known to be associated with poor prognosis in DLBCL patients, including SOCS1 non-truncating mutations and mutations in CREBBP and FOX01<ref name=":9" />. HGBL DH/TH also shows a significantly higher number of IGH and MYC mutations than DLBCL with isolated MYC translocation<ref name=":8" />. MYC hotspot mutations occur more frequently in cases in which the MYC translocation partner is an immunoglobulin gene, and are associated with high MYC protein expression<ref name=":12" />. Amongst the most frequently mutated genes, somatic CREBBP mutations have been shown to inhibit TP53 tumour suppressor activity through activation of the BCL6 oncoprotein<ref name=":9" />. KMT2D mutations consist primarily of frameshift deletions and stop gain alterations with subsequent loss of protein function<ref name=":9" />.

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==Genes and Main Pathways Involved==

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Put your text here and fill in the table (''Instructions: Can include references in the table.'')

{| class="wikitable sortable"

|-

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

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|~~~~EXAMPLE:~~~~ BRAF and MAP2K1; Activating mutations

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|EXAMPLE: BRAF and MAP2K1; Activating mutations

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|~~~~EXAMPLE:~~~~ MAPK signaling

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|EXAMPLE: MAPK signaling

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|~~~~EXAMPLE:~~~~ Increased cell growth and proliferation

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|EXAMPLE: Increased cell growth and proliferation

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|~~~~EXAMPLE:~~~~ CDKN2A; Inactivating mutations

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|EXAMPLE: CDKN2A; Inactivating mutations

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|~~~~EXAMPLE:~~~~ Cell cycle regulation

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|EXAMPLE: Cell cycle regulation

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|~~~~EXAMPLE:~~~~ Unregulated cell division

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|EXAMPLE: Unregulated cell division

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|~~~~EXAMPLE:~~~~ KMT2C and ARID1A; Inactivating mutations

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|EXAMPLE: KMT2C and ARID1A; Inactivating mutations

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|~~~~EXAMPLE:~~~~ Histone modification, chromatin remodeling

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|EXAMPLE: Histone modification, chromatin remodeling

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|~~~~EXAMPLE:~~~~ Abnormal gene expression program

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|EXAMPLE: Abnormal gene expression program

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<blockquote class='blockedit'>{{Box-round|title=~~HAEM5 Conversion Notes~~|~~Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification~~}}

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

MYC is a proto-oncogene located at chromosome 8q24.2 which has been implicated in a variety of human cancers through its role as a regulator of multiple functions including cellular proliferation, DNA and protein synthesis and metabolism<ref>{{Cite journal|last=Cheah|first=Chan Yoon|last2=Oki|first2=Yasuhiro|last3=Westin|first3=Jason R.|last4=Turturro|first4=Francesco|date=2015-03|title=A clinician's guide to double hit lymphomas|url=https://onlinelibrary.wiley.com/doi/10.1111/bjh.13276|journal=British Journal of Haematology|language=en|volume=168|issue=6|pages=784–795|doi=10.1111/bjh.13276}}</ref>. In the process of B cell maturation, MYC is involved in multiple different intracellular pathways governing angiogenesis, differentiation and metabolism<ref name=":27">{{Cite journal|last=Korać|first=Petra|last2=Dotlić|first2=Snježana|last3=Matulić|first3=Maja|last4=Zajc Petranović|first4=Matea|last5=Dominis|first5=Mara|date=2017-04-04|title=Role of MYC in B Cell Lymphomagenesis|url=http://www.mdpi.com/2073-4425/8/4/115|journal=Genes|language=en|volume=8|issue=4|pages=115|doi=10.3390/genes8040115|issn=2073-4425|pmc=PMC5406862|pmid=28375188}}</ref>. MYC, not normally expressed by naïve B cells, is upregulated upon antigen stimulation and is crucial for germinal centre development, but is then subsequently suppressed by BCL6 and BLIMP1<ref>{{Cite journal|last=Karube|first=Kennosuke|last2=Campo|first2=Elias|date=2015-04|title=MYC alterations in diffuse large B-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/25805589|journal=Seminars in Hematology|volume=52|issue=2|pages=97–106|doi=10.1053/j.seminhematol.2015.01.009|issn=1532-8686|pmid=25805589}}</ref>. MYC translocation leads to increased MYC expression compared to non-translocated cases, regardless of translocation partner<ref>{{Cite journal|last=Bertrand|first=P.|last2=Bastard|first2=C.|last3=Maingonnat|first3=C.|last4=Jardin|first4=F.|last5=Maisonneuve|first5=C.|last6=Courel|first6=M.-N.|last7=Ruminy|first7=P.|last8=Picquenot|first8=J.-M.|last9=Tilly|first9=H.|date=2007-03|title=Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/17230227|journal=Leukemia|volume=21|issue=3|pages=515–523|doi=10.1038/sj.leu.2404529|issn=0887-6924|pmid=17230227}}</ref>. Translocation of MYC to an immunoglobulin locus leads to overexpression of the MYC protein due to IG promoter driven constitutively active transcription<ref name=":28">{{Cite journal|last=Sesques|first=Pierre|last2=Johnson|first2=Nathalie A.|date=2017-01-19|title=Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements|url=https://ashpublications.org/blood/article/129/3/280/36006/Approach-to-the-diagnosis-and-treatment-of|journal=Blood|language=en|volume=129|issue=3|pages=280–288|doi=10.1182/blood-2016-02-636316|issn=0006-4971}}</ref>. MYC expression in lymphoma promotes cell proliferation and induces genomic instability<ref name=":28" /><ref>{{Cite journal|last=Meyer|first=Natalie|last2=Penn|first2=Linda Z.|date=2008-12|title=Reflecting on 25 years with MYC|url=http://dx.doi.org/10.1038/nrc2231|journal=Nature Reviews Cancer|volume=8|issue=12|pages=976–990|doi=10.1038/nrc2231|issn=1474-175X}}</ref>, however whilst MYC contributes to oncogenic changes, it can also paradoxically promote apoptosis and increase the expression of tumour suppressor TP53<ref name=":25" /><ref name=":27" />. MYC overexpression in isolation is insufficient to promote lymphomagenesis<ref name=":25">{{Cite journal|last=Riedell|first=Peter A.|last2=Smith|first2=Sonali M.|date=2018-12-15|title=Double hit and double expressors in lymphoma: Definition and treatment|url=https://onlinelibrary.wiley.com/doi/10.1002/cncr.31646|journal=Cancer|language=en|volume=124|issue=24|pages=4622–4632|doi=10.1002/cncr.31646|issn=0008-543X}}</ref><ref name=":27" />, and MYC translocation is postulated to occur as a secondary genetic abnormality contributing to oncogenesis and an aggressive phenotype<ref name=":0" /><ref name=":27" />.

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