Compendium of Cancer Genome Aberrations

HAEM5:T-large granular lymphocytic leukaemia: Difference between revisions

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|WHO, NCCN  
|WHO, NCCN  
|STAT3 mutation has been associated with statistically significant neutropenia, thrombocytopenia, and reduced numbers of most normal residual blood-leukocyte subsets<sup>[22]</sup>  
|STAT3 mutation has been associated with statistically significant neutropenia, thrombocytopenia, and reduced numbers of most normal residual blood-leukocyte subsets<sup>[22]</sup>  




STAT3 mutations are associated with a worse prognosis and reduced overall survival <sup>[1][23]</sup>  
STAT3 mutations are associated with a worse prognosis and reduced overall survival <sup>[1][23]</sup>  




Patients with STAT 3 mutation required treatment more frequently when compared to patients with STAT3 wild type<sup>[18]</sup>  
Patients with STAT 3 mutation required treatment more frequently when compared to patients with STAT3 wild type<sup>[18]</sup>  




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STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12]</sup>  
 
STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12]</sup>
 
17% of patients with STAT3 mutations, had multiple mutations in the STAT3 gene, solely in cytotoxic CD8+ or NK cells.<ref name=":4" />
|-
|-
|STAT5B <sup>[1]</sup> <br />
|STAT5B <sup>[1]</sup> <br />
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Mutations in the inter-domain region: P702A <sup>[19]</sup>  
Mutations in the inter-domain region: P702A <sup>[19]</sup>  
|Other <sup>[32]</sup>  
|Other <sup>[32]</sup>  
|Common <sup>[20]</sup>  
|Rare <sup>[7]</sup>
|D,P,T  
|D,P,T  
|WHO, NCCN  
|WHO, NCCN  
|N642H mutation (associated with more aggressive disease)<sup>[13][14]</sup>  
|N642H mutation (associated with more aggressive disease)<sup>[13][14]</sup>  




Clones can acquire multiple STAT5B mutations <sup>[19]</sup>  
Clones can acquire multiple STAT5B mutations <sup>[19]</sup>  




STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12</sup>
STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12</sup>




N642H mutation is associated with CD3+/CD56+ phenotype<sup>[14]</sup>  
N642H mutation is associated with CD3+/CD56+ phenotype<sup>[14]</sup>  


STAT5B mutations are more common in CD4+ T-LGLL than in CD8+ T-LGLL <sup>[19][20]</sup>
STAT5B mutations are more common in CD4+ T-LGLL than in CD8+ T-LGLL <sup>[19][20]</sup>
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|WHO  
|WHO  
|TNFAIP 3 mutation has been correlated with increased overall survival <sup>[17]</sup>  
|TNFAIP 3 mutation has been correlated with increased overall survival <sup>[17]</sup>  




TNFAIP3 itself is a NF‐κB target gene<sup>[15]</sup>  
TNFAIP3 itself is a NF‐κB target gene<sup>[15]</sup>  


 
In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (''p''  = 0.004)<sup>[9]</sup>
In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (''p''  = 0.004)<sup>[9]</sup>  
|-
|-
|TET2 <sup>[1]</sup>  
|TET2 <sup>[1]</sup>  
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KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation <sup>[26]</sup>  
KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation <sup>[26]</sup>  
|-
|TRAF3 <sup>[30]</sup>
|c.650A>T p.E217V <sup>[30]</sup>
|Other <sup>[39]</sup>
|Rare <sup>[30]</sup>
|N/A
|None
|Mutated putative driver <sup>[30]</sup>
|-
|-
|CLIP3 <sup>[30]</sup>  
|CLIP3 <sup>[30]</sup>  
|
|c.908A>T p.D303V
|
 
|
 
|
c.917A>T p.K306M <sup>[30]</sup>
|
|Other <sup>[40]</sup>
|
|Rare <sup>[30]</sup>
|N/A
|None
|Mutated putative driver <sup>[30]</sup>
|-
|FBXW2 <sup>[30]</sup>
|c.683C>G p.A228G <sup>[30]</sup>
|Other <sup>[41]</sup>
|Rare <sup>[30]</sup>
|N/A
|None
|Mutated putative driver <sup>[30]</sup>
|-
|CREBBP <sup>[30]</sup>
|c.1178A>G p.N393S
 
 
c.4306T>C p.C1436R <sup>[30]</sup>
|Other
|Rare <sup>[30]</sup>
|N/A
|None
|A case is described of CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL<sup>[28]</sup>
A case is described of CCL22 mutation co-occurring with both STAT3 and STAT5B in a CD4+TCR αβ T-LGLL <sup>[28]</sup>
|}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.


<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL.


{| class="wikitable sortable"
{| class="wikitable sortable"
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**An epigenetic inhibition mechanism to SOCS3 gene is hypothesized<ref name=":10" />
**An epigenetic inhibition mechanism to SOCS3 gene is hypothesized<ref name=":10" />
**KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter<ref name=":10" />
**KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter<ref name=":10" />
**Mutations in KMT2D and TET2 have been found to significantly co-occur with STAT3 mutations<sup>[26]</sup>


<br />
<br />
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|JAK/STAT<sup>[7]</sup>  
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|Constitutive activation
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Dysregulation of apoptosis
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|NK-kB<sup>[7]</sup>  
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|Pathway activation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Preventing apoptosis
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|FAS and FASL<sup>[7]</sup>  
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|Resistance to FAS mediated apoptosis
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|Activation of pro-survival pathways which is postulated to lead to neutropenia
|-
|-
|
|RAS/RAF1/MEK1/ERK<sup>[7]</sup>
|
|Overactive RAS
|
|Constitutive activation of RAS and ERK
|-
|PI3K/AKT<sup>[7]</sup>
|Dysregulation
|Apoptosis inhibition
|}
|}


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


*JAK/STAT<ref name=":9" />
**
**Constitutive activation
*NK-κB<ref name=":9" />
**Activation of this pathway
**Preventing apoptosis
*T-LGL's express high levels of FAS and FASL<ref name=":9">Lamy T, Moignet A, Loughran TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017 Mar 2;129(9):1082-94.</ref>
**Resistant to FAS mediated apoptosis
**Leading to activation of prosurvival pathways
**Postulated to lead to neutropenia seen in these patients.
*RAS/RAF1/MEK1/ERK <ref name=":9" />
**Overactive RAS
**Constitutive activation of RAS and ERK
*PI3K/AKT<ref name=":9" />
**Dysregulation
**Contributing to apoptosis inhibition


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==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


*Morphologic assessment, flow cytometry and immunohistochemistry
*Morphologic assessment, flow cytometry and immunohistochemistry  
*PCR to assess for clonality, T-cell receptor (TCR) gene rearrangements
*PCR to assess for clonality, T-cell receptor (TCR) gene rearrangements  
**TCR gamma (TCRG) gene is rearranged in all cases, regardless of the type of TCR expressed, thus proves clonality<ref name=":0" />
** TCR gamma (TCRG) gene is rearranged in all cases, regardless of the type of TCR expressed, thus proves clonality
***Can be helpful in differentiating a reactive lymphocytosis from clonal T-LGL's
** Can be helpful in differentiating a reactive lymphocytosis from clonal T-LGL's  
**NK LGL proliferations do not express TCR, making assessment of clonality difficult<ref name=":9" />
*** NK LGL proliferations do not express TCR, making assessment of clonality difficult
***Expression of activating isoforms of killer immunoglobulin-like receptors (KIR) can be used as a surrogate marker of clonality in NK LGL<ref name=":9" />
*** Expression of activating isoforms of killer immunoglobulin-like receptors (KIR) can be used as a surrogate marker of clonality in NK LGL
* Myeloid neoplasms may present with clonal large granular lymphocyte expansion with STAT3/STAT5B mutations. Next generation sequencing can be diagnostically useful in these cases<sup>[21]</sup>  


==Familial Forms==
==Familial Forms==
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==Additional Information==
==Additional Information==


*N/A
*PI3K-Akt has been found to be upregulated in KLRG1<sup>-</sup> CD8<sup>+</sup> T-LGLL. Studies are being conducted to examine treatment with linperlisib.<sup>[29]</sup>  
*Myleoid clonal hematopoiesis is associated with the presence of cytopenia in LGLL<sup>[30]</sup>


==Links==
==Links==
Retrieved from "https://test.ccga.io/index.php/HAEM5:T-large_granular_lymphocytic_leukaemia"