Compendium of Cancer Genome Aberrations

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

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==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>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>{{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=":3">{{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> 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><ref name=":3" />
{| 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
|
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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>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 proteins, mRNA, and other elements.<ref>{{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> NUP98 fusion proteins typically involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner. 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.<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]'''
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|-
|-
|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''
|}
|}


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|}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  
 
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'''
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|'''Clinical Relevance Details/Other Notes'''
|'''Clinical Relevance Details/Other Notes'''
|-
|-
|''FLT3-ITD''
|''FLT3''
|
|Internal tandem duplication
|
|Oncogene
|Recurrent
|Common (frequency varies with fusion partner)
|Poor prognosis
|P,T
|
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|Seen in 67  to 91% of cases with NUP98::NSD1
|Seen in 67  to 91% of cases with NUP98::NSD1
|-
|-
|''WT1''
|''WT1''
|Gain or loss of function
|Oncogene/Tumor Suppressor Gene
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|Rare
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|Reported in  33-55% of NUP98::NSD1 rearranged AML
|Reported in  33-55% of NUP98::NSD1 rearranged AML
|-
|''RB1''
|
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|Rare
|
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|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==
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