Compendium of Cancer Genome Aberrations

HAEM5:Aggressive NK-cell leukaemia: Difference between revisions

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==WHO Classification of Disease==
==WHO Classification of Disease==


Aggressive NK-cell leukaemia
Aggressive NK-cell Leukaemia


==Definition / Description of Disease==
==Definition / Description of Disease==
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==Epidemiology / Prevalence==
==Epidemiology / Prevalence==
Aggressive NK-cell leukaemia impacts young to middle-aged adults with peak incidence during 3rd and 5th decades of life (Mean age: 40 years).<ref name=":1" /> There is no gender predilection and most prevalent in Asia, Central and South America.<ref name=":0">{{Cite journal|last=El Hussein|first=Siba|last2=Patel|first2=Keyur P.|last3=Fang|first3=Hong|last4=Thakral|first4=Beenu|last5=Loghavi|first5=Sanam|last6=Kanagal-Shamanna|first6=Rashmi|last7=Konoplev|first7=Sergej|last8=Jabbour|first8=Elias J.|last9=Medeiros|first9=L. Jeffrey|date=09 2020|title=Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32590457|journal=The American Journal of Surgical Pathology|volume=44|issue=9|pages=1235–1243|doi=10.1097/PAS.0000000000001518|issn=1532-0979|pmid=32590457}}</ref> EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations.<ref name=":2" /> Median survival is very short, <2 months.
Aggressive NK-cell leukaemia impacts young to middle-aged adults with peak incidence during 3rd and 5th decades of life (Mean age: 40 years).<ref name=":1" /> There is no gender predilection and most prevalent in Asia, Central and South America.<ref name=":0">{{Cite journal|last=El Hussein|first=Siba|last2=Patel|first2=Keyur P.|last3=Fang|first3=Hong|last4=Thakral|first4=Beenu|last5=Loghavi|first5=Sanam|last6=Kanagal-Shamanna|first6=Rashmi|last7=Konoplev|first7=Sergej|last8=Jabbour|first8=Elias J.|last9=Medeiros|first9=L. Jeffrey|date=09 2020|title=Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32590457|journal=The American Journal of Surgical Pathology|volume=44|issue=9|pages=1235–1243|doi=10.1097/PAS.0000000000001518|issn=1532-0979|pmid=32590457}}</ref> Median survival is very short, <2 months. EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations.<ref name=":2" /> EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells.'''''<ref name=":4" />'''''




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==Clinical Features==
==Clinical Features==


Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.<ref name=":1" /><ref name=":4" />
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|'''Signs and Symptoms'''
|Constitutional symptoms (weight loss, fever, night sweats)
|Constitutional symptoms (weight loss, fever, night sweats)


Hepatosplenomegaly common<ref name=":1" />
Hepatosplenomegaly common


Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
'''''<nowiki>*</nowiki>EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells<ref name=":4" />'''''
|-
|-
|'''Laboratory Findings'''
|'''Laboratory Findings'''
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==Sites of Involvement==
==Sites of Involvement==


Peripheral blood, bone marrow, liver, spleen, and lymph nodes. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum can be seen.<ref name=":5" />
Peripheral blood, bone marrow, liver, spleen, and lymph nodes are frequently involved. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum has also been reported.<ref name=":5" />




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==Immunophenotype==
==Immunophenotype==


The leukaemic cells .......
The leukaemic cells show demonstrate the following phenotypic expression.<ref name=":1" /><ref name=":0" />
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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==Chromosomal Rearrangements (Gene Fusions)==
==Chromosomal Rearrangements (Gene Fusions)==


Put your text here and fill in the table
Due to the rarity of this lymphoma the data in recurrent chromosomal rearrangement is extremely scant. There have been chromosomal rearrangements reported in association with the aggressive NK-cell leukaemia, however, none of them are considered specific for the disease.


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
!Notes
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference)
|Yes
|No
|Yes
|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=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref>{{Cite journal|last=Dufva|first=Olli|last2=Kankainen|first2=Matti|last3=Kelkka|first3=Tiina|last4=Sekiguchi|first4=Nodoka|last5=Awad|first5=Shady Adnan|last6=Eldfors|first6=Samuli|last7=Yadav|first7=Bhagwan|last8=Kuusanmäki|first8=Heikki|last9=Malani|first9=Disha|date=04 19, 2018|title=Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target|url=https://pubmed.ncbi.nlm.nih.gov/29674644|journal=Nature Communications|volume=9|issue=1|pages=1567|doi=10.1038/s41467-018-03987-2|issn=2041-1723|pmc=5908809|pmid=29674644}}</ref></blockquote>
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":6">{{Cite journal|last=Dufva|first=Olli|last2=Kankainen|first2=Matti|last3=Kelkka|first3=Tiina|last4=Sekiguchi|first4=Nodoka|last5=Awad|first5=Shady Adnan|last6=Eldfors|first6=Samuli|last7=Yadav|first7=Bhagwan|last8=Kuusanmäki|first8=Heikki|last9=Malani|first9=Disha|date=04 19, 2018|title=Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target|url=https://pubmed.ncbi.nlm.nih.gov/29674644|journal=Nature Communications|volume=9|issue=1|pages=1567|doi=10.1038/s41467-018-03987-2|issn=2041-1723|pmc=5908809|pmid=29674644}}</ref></blockquote>
</blockquote>
</blockquote>
==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 fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>
There have been a few chromosomal abnormalities associated with aggressive NK-cell leukaemia as listed below, however, the specificity along with prognostic and therapeutic significance is unknown.<ref name=":2" />


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Notes
!Notes
|-
|-
|EXAMPLE
|1
 
|Gain
7
|1q23.1-q23.2
|EXAMPLE Loss
|
|EXAMPLE
|No
 
|Unknown
chr7:1- 159,335,973 [hg38]
|Unknown
|EXAMPLE
|
 
|-
chr7
|1
|Yes
|Gain
|Yes
|1q31.3-q44
|
|No
|No
|EXAMPLE
|Unknown
 
|Unknown
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).
|
|-
|-
|EXAMPLE
|7
 
|Loss
8
|7p15.1-q22.3
|EXAMPLE Gain
|
|EXAMPLE
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
|No
|No
|Unknown
|Unknown
|
|-
|17
|Loss
|17p13.1
|
|No
|No
|Unknown
|Unknown
|
|-
|6
|Loss
|6q16.1–q27
|
|No
|No
|EXAMPLE
|Unknown
 
|Unknown
Common recurrent secondary finding for t(8;21) (add reference).
|
|}
|}


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==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal Patterns==


Put your text here <span style="color:#0070C0">(''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'')</span>
Due to rare nature of disease, cytogenetics data is limited. The common abnormalities include del(6)(q21q25) and del(11q), however, none of these abnormalities are specific and their clinical significance is unknown.<ref name=":2" /> Complex karyotypes with unbalanced rearrangements are frequently seen.


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
!Notes
|-
|EXAMPLE
Co-deletion of 1p and 18q
|Yes
|No
|No
|EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
|}


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</blockquote>
</blockquote>
==Gene Mutations (SNV / INDEL)==
==Gene Mutations (SNV / INDEL)==
Mutations in the ''JAK-STAT'' pathway appear to be mutually exclusive.<ref name=":3" /> Most ''STAT3'' and ''STAT5B''  mutations localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain, which causes ''STAT'' dimerization. Other mutations identified: 9p copy gains (containing ''JAK2),'' point mutation in protein tyrosine phosphatase (''PTPRK'') (tumor suppressor that negatively regulates ''STAT3''). mutations in ''PTPN4'' and ''PTPN23.<ref name=":2" /><ref name=":7" />''


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 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.'') </span>
Molecular abnormalities present possible therapeutic implications. Dufva et al identified high sensitivity of ANKL cell lines to JAK and BCL2 inhibition. Other possibly effective drug classes are heat shock protein 90 (HSP90) inhibitors, polo-like kinase (PLK) inhibitors, aurora kinase (AURK) inhibitors, cyclin-dependent kinase inhibitors, and histone deacetylase inhibitors.<ref name=":6" />


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Notes
!Notes
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|JAK/STAT/c-MYC pathway (including ''STAT3, STAT5B, STAT5A, JAK2, JAK3, STAT6, SOCS31, SOCS3'' and ''PTPN11'')
 
|Oncogene
EXAMPLE:
|21 - 66.6%
 
|
EGFR; Exon 20 mutations
|
 
EXAMPLE: BRAF; Activating mutations
|EXAMPLE: TSG
|EXAMPLE: 20% (COSMIC)
 
EXAMPLE: 30% (add Reference)
|EXAMPLE: IDH1 R123H
|EXAMPLE: EGFR amplification
|
|
|
|
|
|
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|Gain of function
<br />
<br />
|-
|RAS/MAPK pathway
|Oncogene
|16.7 - 29%
|
|
|
|
|
|Gain of function
|-
|''TP53''
|Tumor suppressor gene
|7 -50%
|
|
|
|
|
|Loss of function
|-
|''BCL2''
|Oncogene
|NA
|
|
|
|
|
|Gain of function
|}
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) 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 cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
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<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":2">{{Cite journal|last=El Hussein|first=Siba|last2=Medeiros|first2=L. Jeffrey|last3=Khoury|first3=Joseph D.|date=10 09, 2020|title=Aggressive NK Cell Leukemia: Current State of the Art|url=https://pubmed.ncbi.nlm.nih.gov/33050313|journal=Cancers|volume=12|issue=10|doi=10.3390/cancers12102900|issn=2072-6694|pmc=7600035|pmid=33050313}}</ref><ref>{{Cite journal|last=Gao|first=Juehua|last2=Zhang|first2=Yanming|last3=Yaseen|first3=Nabeel R.|last4=Fang|first4=Yuqiang|last5=Lu|first5=Xinyan|last6=Sukhanova|first6=Madina|last7=Chen|first7=Qing|last8=Chen|first8=Yi-Hua|date=2020-11|title=Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma|url=https://linkinghub.elsevier.com/retrieve/pii/S0046817720301702|journal=Human Pathology|language=en|volume=105|pages=20–30|doi=10.1016/j.humpath.2020.08.008}}</ref><ref name=":3" /></blockquote>
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":2">{{Cite journal|last=El Hussein|first=Siba|last2=Medeiros|first2=L. Jeffrey|last3=Khoury|first3=Joseph D.|date=10 09, 2020|title=Aggressive NK Cell Leukemia: Current State of the Art|url=https://pubmed.ncbi.nlm.nih.gov/33050313|journal=Cancers|volume=12|issue=10|doi=10.3390/cancers12102900|issn=2072-6694|pmc=7600035|pmid=33050313}}</ref><ref name=":7">{{Cite journal|last=Gao|first=Juehua|last2=Zhang|first2=Yanming|last3=Yaseen|first3=Nabeel R.|last4=Fang|first4=Yuqiang|last5=Lu|first5=Xinyan|last6=Sukhanova|first6=Madina|last7=Chen|first7=Qing|last8=Chen|first8=Yi-Hua|date=2020-11|title=Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma|url=https://linkinghub.elsevier.com/retrieve/pii/S0046817720301702|journal=Human Pathology|language=en|volume=105|pages=20–30|doi=10.1016/j.humpath.2020.08.008}}</ref><ref name=":3" /></blockquote>
</blockquote>
</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==


 
Mutations seen in epigenetic regulatory molecules including RNA helicase ''DDX3X'' (28%), ''TET2'' (28%), ''CREBBP'' (21%), and ''MLL2'' (21%) have been reported.<ref name=":2" /><ref name=":3" />
Mutations seen in epigenetic regulatory molecules:
 
*RNA helicase ''DDX3X'' (28%)
*''TET2'' (28%)
*''CREBBP'' (21%)
*''MLL2'' (21%)




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==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
The disease pathogenesis is regulated by a complex interplay between diverse molecular pathways especially that involving the upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.<ref name=":2" />
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|STAT3 activation of the MYC transcription program
|EXAMPLE: MAPK signaling
|JAK/STAT-MYC biosynthesis axis
|EXAMPLE: Increased cell growth and proliferation
|Increased cell survival and proliferation
|-
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|Alterations in RAS-MAPK pathway
|EXAMPLE: Cell cycle regulation
|RAS-MAPK pathway
|EXAMPLE: Unregulated cell division
|Increased cell survival and proliferation
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|''BCOR, KMT2D/MLL2'', ''SETD2'', ''PRDM9'', ''CREBBP'', and ''TET2''
|EXAMPLE:  Histone modification, chromatin remodeling
|Epigenetic modifier genes
|EXAMPLE:  Abnormal gene expression program
|Altering the epigenetic landscape
|-
|''TP53, ASXL1, ASXL2, BRINP3''
|DNA damage repair
|??
|-
|''PRPF40B''
|mRNA splicing factors
|??
|}
|}


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<nowiki>*</nowiki>Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.
<nowiki>*</nowiki>Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.<ref name=":2" />




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


 
Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.<ref name=":0" />
Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.




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