Compendium of Cancer Genome Aberrations

HAEM5:Acute myeloid leukaemia with NUP98 rearrangement: Difference between revisions

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{{DISPLAYTITLE:Acute myeloid leukaemia with NUP98 rearrangement}}
{{DISPLAYTITLE:Acute myeloid leukaemia with NUP98 rearrangement}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
{{Under Construction}}
<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)*==
==Primary Author(s)*==


Eric McGinnis, MD
Eric McGinnis, MD, Vancouver General Hospital


Fatma Albulushi, MD
Fatma Albulushi, MD, University Medical City
==WHO Classification of Disease==
==WHO Classification of Disease==


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|}
|}


==WHO Essential and Desirable Genetic Diagnostic Criteria.==
{| class="wikitable"
|WHO Essential Criteria  (Genetics)*
|Detection of NUP98 rearrangement
|-
|WHO Desirable Criteria  (Genetics)*
|Identification of the NUP98 fusion  partner
|-
|Other Classification
|Myeloid blast count may <20%
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.
==Related Terminology==
==Related Terminology==


Line 57: Line 44:


==Gene Rearrangements==
==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>
Acute myeloid leukemia (AML) with ''NUP98'' rearrangement is characterized by chromosomal translocations involving ''NUP98'' (nucleoporin 98 and 96 precursor) on chromosome 11p15.4 and various partner genes - more than 40 of such have been reported to date.<ref name=":5">Patkar N, Meshinchi S, Westerman D, et al. Acute myeloid leukaemia with NUP98 rearrangement. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Lyon (France): International Agency for Research on Cancer; 2024. . (WHO classification of tumours series, 5th ed.; vol. 11). <nowiki>https://publications.iarc.who.int/637</nowiki>.</ref> The ''NUP98'' gene encodes protein component of the nuclear pore complex which facilitates nucleocytoplasmic transport of RNA and has roles in transcriptional and cell cycle regulation.<ref name=":2">{{Cite journal|last=Gough|first=Sheryl M.|last2=Slape|first2=Christopher I.|last3=Aplan|first3=Peter D.|date=2011-12-08|title=NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights|url=https://pubmed.ncbi.nlm.nih.gov/21948299|journal=Blood|volume=118|issue=24|pages=6247–6257|doi=10.1182/blood-2011-07-328880|issn=1528-0020|pmc=3236115|pmid=21948299}}</ref><ref name=":4">{{Cite journal|last=Michmerhuizen|first=Nicole L.|last2=Klco|first2=Jeffery M.|last3=Mullighan|first3=Charles G.|date=2020-11-12|title=Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies|url=https://pubmed.ncbi.nlm.nih.gov/32766874|journal=Blood|volume=136|issue=20|pages=2275–2289|doi=10.1182/blood.2020007093|issn=1528-0020|pmc=7702474|pmid=32766874}}</ref> NUP98 fusion proteins typically involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner.<ref name=":2" /> Fusion partners commonly include transcription factors (such as ''HOX'' elements, most often ''HOXA9'') or epigenetic regulators (most commonly involving ''NSD1'' or ''KDM5A''), however a range of partners belonging to neither of these categories has been identified, many of which contain coiled-coil domains thought to facilitate oligomerization.<ref name=":0">{{Cite journal|last=Mohanty|first=Sagarajit|date=2023-09|title=NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications|url=https://www.mdpi.com/2673-7523/3/3/11|journal=Onco|language=en|volume=3|issue=3|pages=147–164|doi=10.3390/onco3030011|issn=2673-7523}}</ref>
{| 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''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<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''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> 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''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
 
 
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>
 
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|
|
|
|
|
|
|
|
|}
 
Acute myeloid leukaemia (AML) with NUP98 rearrangement is characterized by chromosomal translocations involving NUP98 (nucleoporin 98 kDa) on chromosome 11p15.4 and various partner genes. (Reference WHO book). There are over 40 fusion partners which have been reported to date. NUP98 fusions can be categorized into three broad parts. The first category includes NUP98 fusions with transcription factors as partners, which can change the expression of target genes through DNA binding domains. The second category is NUP98 fusions with epigenetic modifiers that modify chromatin to change target gene expression. The third category of NUP98 fusions has neither the DNA binding nor chromatin remodeling domain.<ref name=":0">{{Cite journal|last=Mohanty|first=Sagarajit|date=2023-09|title=NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications|url=https://www.mdpi.com/2673-7523/3/3/11|journal=Onco|language=en|volume=3|issue=3|pages=147–164|doi=10.3390/onco3030011|issn=2673-7523}}</ref>  
 
 
The NUP98 gene (chromosome 11p15) encodes a nucleoporin protein, which is part of the nuclear pore complex which regulates nucleocytoplasmic transport of protein and RNA. NUP98 fusion proteins involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner. These fusion partners consist of homeodomain proteins, which are transcription factors, and non-homeodomain proteins, which are thought to play a role in transcriptional or epigenetic regulation.<ref name=":0" /><ref name=":1">{{Cite journal|last=Bertrums|first=Eline J. M.|last2=Smith|first2=Jenny L.|last3=Harmon|first3=Lauren|last4=Ries|first4=Rhonda E.|last5=Wang|first5=Yi-Cheng J.|last6=Alonzo|first6=Todd A.|last7=Menssen|first7=Andrew J.|last8=Chisholm|first8=Karen M.|last9=Leonti|first9=Amanda R.|date=2023-02-23|title=Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia|url=https://www.haematologica.org/article/view/haematol.2022.281653|journal=Haematologica|language=en|volume=108|issue=8|pages=2044–2058|doi=10.3324/haematol.2022.281653|issn=1592-8721}}</ref>
<br />
{| class="wikitable"
{| class="wikitable"
|'''Driver Gene'''
|'''Driver Gene'''
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|''NUP98''
|''NUP98''
|''NUP98::NSD1''
|''NUP98::NSD1''
<br />
|Fusion of N-terminal ''NUP98'' (with fusion junction most often involving exons 12-13) to C-terminal ''NSD1''; fusion proteins result in epigenetic modification and dysregulation of ''HOXA''/''HOXB'' family genes, among others, through functional domains in both fusion partners.
|NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation  at regulatory DNA elements hence preventing myeloid progenitor immortalization.
|t(5;11)(q35;p15)
|t(5;11)(q35;p15)


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|Rare (AML)
|Rare (AML)
|Defining genetic abnormality in AML
|Defining genetic abnormality in AML
|Yes (WHO)
|Yes (WHO/ICC)
|Rare but recurrent alteration seen mainly in children and young adults with AML. Poor overall survival, disease free survival, induction  failure and chemotherapy resistance.<ref name=":1" />
|Rare though most common recurrent NUP98 rearrangement in children and young adults.<ref name=":1">{{Cite journal|last=Bertrums|first=Eline J. M.|last2=Smith|first2=Jenny L.|last3=Harmon|first3=Lauren|last4=Ries|first4=Rhonda E.|last5=Wang|first5=Yi-Cheng J.|last6=Alonzo|first6=Todd A.|last7=Menssen|first7=Andrew J.|last8=Chisholm|first8=Karen M.|last9=Leonti|first9=Amanda R.|date=2023-02-23|title=Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia|url=https://www.haematologica.org/article/view/haematol.2022.281653|journal=Haematologica|language=en|volume=108|issue=8|pages=2044–2058|doi=10.3324/haematol.2022.281653|issn=1592-8721}}</ref>
|-
|-
|''NUP98''
|''NUP98''
|''NUP98::KDM5A''
|''NUP98::KDM5A''
|KDM5A is an epigenetic-modifying partners of NUP98 which  dysregulate Hox genes expression through recognition of H3K4me3/2  marks by the plant homeodomain (PHD) finger domain.
|Fusion of N-terminal ''NUP98'' (fusion junction most often involving exons 13-14) to C-terminal ''KDM5A;'' fusion proteins result in epigenetic modification and dysregulation of ''HOXA''/''HOXB'' family genes, among others, through functional domains in both fusion partners.
|t(11;12)(p15;p13)
|t(11;12)(p15;p13)


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|Rare (AML)
|Rare (AML)
|Defining genetic abnormality in AML
|Defining genetic abnormality in AML
|Yes (WHO)
|Yes (WHO/ICC)
|''Commonly associated with erythroid and megakaryocytic phenotypes  in pediatric AML (acute erythroid leukemia and acute megakaryocytic  leukemia).''<ref name=":1" />  
|Commonly associated with erythroid and megakaryocytic phenotypes  in pediatric AML (acute erythroid leukemia and acute megakaryocytic  leukemia). <ref name=":1" />
 
''Usually associate with unfavorable outcomes''
|-
|-
|''NUP98''
|''NUP98''
|''NUP98::HOXA9''
|''NUP98::HOXA9''
<br />
|Fusion of N-terminal ''NUP98'' (fusion junction most often involving exons 13-14) to C-terminal ''HOXA9;'' fusion proteins result in epigenetic modification and dysregulation of ''HOXA''/''HOXB'' family genes, among others, through functional domains in both fusion partners.
|NUP98 fusions bind near the HOX genes  loci and activate their expression through chromatin remodeling. The overexpression  of distal HoxA cluster genes promote self-renewal and drive  leukogenesis.
|t(7;11)(p15;p15)
|t(7;11)(p15, p15)
|Rare (AML)
|Rare (AML)
|Defining genetic abnormality in AML
|Defining genetic abnormality in AML
|
|Yes (WHO/ICC)
|
|
|}
|}


==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 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
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<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).
|-
|<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 characteristic chromosomal gain or loss. However, trisomy 8 and chromosome 13 abnormalities may be observed.
Several reports indicated that del(13q) is a frequent event in ''NUP98::KDM5A'' AML patients, indicating co-occurrence of ''NUP98-KDMA'' fusion with ''RB1'' deletion.
<br />
{| class="wikitable"
{| class="wikitable"
|'''Chromosome Number'''
|'''Chr#'''
|'''Gain/Loss/Amp/LOH'''
|'''Gain/Loss/Amp/LOH'''
|'''Minimal Region Cytoband and/or Genomic  Coordinates [Genome Build; Size]'''
|'''Minimal Region Cytoband and/or Genomic  Coordinates [Genome Build; Size]'''
Line 244: Line 106:
|-
|-
|13
|13
|loss
|Loss
|Deletion of 13q
|13q14.2q14.3<ref name=":2" />
|RB1 gene
|''RB1''
|NA
|NA
|
|No
|Particularly associated with NUP98::KDM5A
|Highly enriched in ''NUP98::KDM5A''
|}
|}


==Characteristic Chromosomal or Other Global Mutational Patterns==
==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"
{| class="wikitable sortable"
|-
|-
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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
|<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
|
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|-
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|}
|}
==Gene Mutations (SNV/INDEL)==
==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
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|<span class="blue-text">EXAMPLE:</span> T
|<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).
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<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
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|}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.
FLT3-ITD and WT1 mutation are recurring events in NUP98::NSD1 and was also observed in some NUP98::HOXA9 AML patients.(R1). Loss of RB1 at 13q14 is particularly associated with NUP98::KDM5A
{| class="wikitable"
{| class="wikitable"
|'''Gene'''
|'''Gene'''
Line 345: Line 142:
|'''Clinical Relevance Details/Other Notes'''
|'''Clinical Relevance Details/Other Notes'''
|-
|-
|''FLT3-ITD''
|''FLT3''
|
|Internal tandem duplication
|
|Oncogene
|Recurrent
|Recurrent-Common (frequency varies with fusion partner)
|Poor prognosis
|P,T
|
|Yes (ELN 2022; independent of fusion)
|Seen in 67  to 91% of cases with NUP98::NSD1
|High frequency in AML with ''NUP98::NSD1''; reported association with adverse prognosis specifically in context of ''NUP98::NSD1''<ref name=":4" />
|-
|-
|''WT1''
|''WT1''
|Gain or loss of function
|Oncogene/Tumor Suppressor Gene
|Recurrent-Common (frequency varies with fusion partner)
|
|
|No
|High frequency in AML with ''NUP98::NSD1;'' reported association with adverse prognosis specifically in context of ''NUP98::NSD1''<ref name=":4" />
|-
|''KRAS''
|Gain of function
|Oncogene
|Recurrent
|
|
|Rare
|No
|
|
|
|Reported in  33-55% of NUP98::NSD1 rearranged AML
|-
|-
|''RB1''
|''NRAS''
|
|Gain of function
|
|Oncogene
|Rare
|Recurrent
|
|
|No
|
|
|Particularly associated with  NUP98::KDM5A
|}
|}
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.


==Epigenomic Alterations==
==Epigenomic Alterations==


 
NUP98 fusion proteins are understood to generally mediate leukemogenesis through the functions of protein domains present in wild-type ''NUP98'' and the relevant fusion partner (often harbouring transcriptional or chromatin-modifying properties); ''in vitro'' experiments have demonstrated chromatin remodeling related to fusion oncoprotein expression (and associated with coordination of numerous interacting proteins, including transcriptional cofactors (e.g. EP300, CREBBP, MEIS1) and histone-modifying complexes) resulting in dysregulation of expression of members of the ''HOXA'' and ''HOXB'' gene families, among other loci (e.g. ''MEIS1'').<ref name=":4" /><ref name=":5" />
Put your text here
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|Various ''NUP98'' fusions
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|HOX-family pathways
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Disruption of critical hematopoietic regulator; dysregulation of differentiation, proliferation, apoptosis, and cell survival.<ref name=":3">{{Cite journal|last=Rasouli|first=Milad|last2=Troester|first2=Selina|last3=Grebien|first3=Florian|last4=Goemans|first4=Bianca F.|last5=Zwaan|first5=C. Michel|last6=Heidenreich|first6=Olaf|date=2024-09|title=NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities|url=https://pubmed.ncbi.nlm.nih.gov/39323480|journal=HemaSphere|volume=8|issue=9|pages=e70013|doi=10.1002/hem3.70013|issn=2572-9241|pmid=39323480}}</ref>
|-
|<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
|-
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|
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


Rearrangements involving NUP98 are often cryptic on conventional karyotype, owing to terminal location of NUP98 on chromosome 11p15.4. Most patients have a normal karyotype. Diagnosis is established using the following tests:
Several common rearrangements involving ''NUP98'' (with ''NSD1'' and ''KDM5A'') are generally cryptic in conventional karyotyping owing to the terminal locations of loci involved, while other rearrangements involving ''NUP98'' may be visible in banded chromosomes.<ref name=":5" /><ref name=":1" /> The following techniques may be used to facilitate detection of cryptic rearrangements:


*FISH using NUP98 break-apart probes
*FISH (e.g. locus-specific ''NUP98'' break-apart probe)
*RT-PCR for fusion proteins like NUP98::NSD1
*RT-PCR assays for detection of specific fusions
*RNA sequencing
*RNA sequencing
*Optical Genome Mapping (OGM)
*Optical genome mapping<br />
 
[[File:NUP98 NSD1 OGM panel figure.png|none|thumb|617x617px|Cytogenetically cryptic ''NUP98::NSD1'' rearrangement detected by optical genome mapping. '''Panel A''': Circos plot depicting t(5;11)(q35.3;p15.4) with inset of chromosomes 5 and 11 showing no visible abnormalities in banded chromosomes. '''Panel B''': ''NUP98::NSD1'' fusion variant call. '''Panel C''': Concurrent deletion of ''WT1''; abnormalities of ''WT1'' are highly recurrent in AML with ''NUP98::NSD1''.]]
<br />
[[File:NUP98 NSD1.png|none|thumb|617x617px|Karyotype image of NUP98 rearranged acute myeloid leukemia. Due to the cryptic nature of NUP98 rearrangement, karyotype is usually normal. ]]
[[File:T(5;11).jpg|none|thumb|584x584px|Optical genome mapping. Figure A showing circus plot with t(5;11). Figure B showing exact breakpoints of the translocation leading to NUP98::NSD1 fusion. Figure C showing WT1 deletion which is a common secondary event in NUP98 rearranged AML.]]
<br />


==Familial Forms==
==Familial Forms==


 
Not applicable.
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
==Additional Information==
==Additional Information==


<br />
''NUP98'' fusions are not specific for ''de novo'' acute myeloid leukemia, also occurring in T-lymphoblastic leukemia and blast phase chronic myeloid leukemia with overlap in the profile of ''NUP98'' fusion partners (though ''HOX'' fusions appear, in reports to date, to be specific to myeloid neoplasms).<ref name=":2" /><ref name=":3" />


==Links==
==Links==


 
Not applicable.
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==References==
==References==
<references />


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==Notes==
==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.
<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.
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[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases A]]
[[Category:Diseases A]]
<references />
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