Compendium of Cancer Genome Aberrations

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

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|N/A||N/A||N/A||N/A
|N/A||N/A||N/A||N/A
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|N/A
|<span class="blue-text">EXAMPLE:</span> D, P, T
|N/A
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|N/A
|<span class="blue-text">EXAMPLE:</span>
|N/A
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).
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*No known chromosomal rearrangements
*


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* Gene Mutations (SNV/INDEL)}}</blockquote>
* Gene Mutations (SNV/INDEL)}}</blockquote>


*There are no FDA approved targeted therapies for T-LGL
*
*STAT3 mutations can be used to follow-up, in response to treatment<ref name=":4" />
**Take caution as STAT mutations are not specific to T-LGL and can be seen in other T-cell lymphomas
*STAT3 mutation, Y640F, has a predicted response to initial therapy with methotrexate<ref>Loughran TP, Zickl L, Olson TL, Wang V, Zhang D, Rajala HL, Hasanali Z, Bennett JM, Lazarus HM, Litzow MR, Evens AM. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia. 2015 Apr;29(4):886-94.</ref>
*Bortezomib is considered due to NF-κB  constitutive activity in T-LGL leukemia<ref>Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, Schaefer D, Falkenberg LG, Sullivan L, Jaroncyk L, Yang X. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer cell. 2012 Nov 13;22(5):645-55.</ref>


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


 
No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in a few cases.<sup>[7]</sup> <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>
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
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|<span class="blue-text">EXAMPLE:</span>
|N/A
7
|N/A
|<span class="blue-text">EXAMPLE:</span> Loss
|N/A
|<span class="blue-text">EXAMPLE:</span>
|N/A
chr7
|N/A
|<span class="blue-text">EXAMPLE:</span>
|N/A
Unknown
|N/A
|<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).
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|<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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*No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in few cases<ref name=":9" />
*


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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>
 
No characteristic chromosomal patterns have been identified. One reported case with unique cytogenetic findings of a γδ variant T-cell LGL include: interstitial deletion of 3p21.31, monosomy X, trisomy 5, monosomy 21, and CN-LOH, located at 17q.
 
<sup>[8]</sup> <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>
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|N/A
Co-deletion of 1p and 18q
|N/A
|<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).
|N/A
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|N/A
|<span class="blue-text">EXAMPLE:</span> D, P
|N/A
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|N/A
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|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
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|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
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*No characteristic chromosomal aberrations have been identified
*Unique cytogenetic findings include:  <small>(reported in one case report of γδ variant T-cell LGL)</small><ref name=":3" />
**Interstitial deletion of 3p21.31, monosomy X, trisomy 5, monosomy 21, and CN‐LOH located at 17q<ref name=":3">Zhang L, Ramchandren R, Papenhausen P, Loughran TP, Sokol L. Transformed aggressive γδ‐variant T‐cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11. 2q25. 3 and additional aberrations. European journal of haematology. 2014 Sep;93(3):260-4.</ref>
***
***


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==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==


 
Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL.  <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>
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''STAT3'' <sup>[1]</sup>
|Gain of function in src-like homologue 2 (SH2) domain of STAT 3, frequently affecting codons Y640 or D661<sup>[1].</sup> Codons N647I<sup>[9]</sup>,K658S<sup>[9]</sup>, and K658F<sup>[22]</sup> are also affected
|Other <sup>[31]</sup>
|Common <sup>[11]</sup>
|D, P, T
|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 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>
 
 
One prospective study showed a predictive response to methotrexate therapy in a small group of patients with STAT3 Y640F mutated genotype<sup>[25]</sup>
 
 
STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12]</sup>
|-
|STAT5B <sup>[1]</sup> <br />
|Gain of function src-like homologue 2 (SH2) domain of STAT5.
Mutations include<sup>[19]</sup>:
N642H
Y665F
Q706L
S715F
T628S
P685R
 
V712E mutation of STAT5B is in the transactivation domain<sup>[19]</sup>
 
Mutations in the coiled-coil domain: CCD, Q220H <sup>[19]</sup>  
 
Mutations in the DNA binding domain: DBD, E433G/K <sup>[19]</sup>  
 
Mutations in the inter-domain region: P702A <sup>[19]</sup>
|Other <sup>[32]</sup>
|Common <sup>[20]</sup>
|D,P,T
|WHO, NCCN
|N642H mutation (associated with more aggressive disease)<sup>[13][14]</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>
 
 
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>
|-
|TNFAIP3 <sup>[1]</sup>
|Loss of function
Somatic mutations:
 
Y353X


<br />
K354K
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
 
|<span class="blue-text">EXAMPLE:</span> Oncogene
Q741
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
 
|<span class="blue-text">EXAMPLE:</span> T
E630X
|<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).
A717T
 
F127C <sup>[9]</sup>
|Other <sup>[33]</sup>  
|Recurrent <sup>[46]</sup>  
|P,T
|WHO
|TNFAIP 3 mutation has been correlated with increased overall survival <sup>[17]</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>  
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|TET2 <sup>[1]</sup>  
<br />
|Loss of function <sup>[26]</sup>  
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Other <sup>[34]</sup>  
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Common <sup>[46]</sup>  
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|N/A
|<span class="blue-text">EXAMPLE:</span> P
|WHO
|
|Found to be the most prevalent mutation in myeloid neoplasm or myeloid clonal hematopoiesis coexisting with T-LGLL <sup>[30]</sup>  
|<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
|BCL11B <sup>[1]</sup>
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Missense H126R <sup>[43]</sup>
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Other <sup>[35]</sup>
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Rare <sup>[43]</sup>
|<span class="blue-text">EXAMPLE:</span> T
|N/A
|
|WHO
|
|BCL11B is required for T-cell survival and overexpression could effectively increase T-cell activation and proliferation. <sup>[43]</sup>
|-
|FLT3 <sup>[1]</sup>
|A high-impact Asp228Gly variant on JAK STAT has been demonstrated <sup>[44]</sup>  
|Other <sup>[36]</sup>
|Rare <sup>[44]</sup>
|N/A
|WHO
|Connects STAT to the MAPK-Ras-ERK pathway and to IL-15 <sup>[44]</sup>  
|-
|PTPN23 <sup>[1]</sup>
|R641Q <sup>[45]</sup>
|Other <sup>[37]</sup>
|Rare <sup>[45]</sup>
|N/A
|WHO
|Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation <sup>[45]</sup>  
|-
|KMT2D <sup>[26]</sup>
|Loss of function <sup>[26]</sup>
|Other <sup>[38]</sup>
|Recurrent <sup>[46]</sup>  
|N/A
|None
|KMT2D has been linked to lymphomagenesis. <sup>[44]</sup>  
 
 
KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation <sup>[26]</sup>
|-
|-
|
|CLIP3 <sup>[30]</sup>
|
|
|
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