Compendium of Cancer Genome Aberrations

HAEM5:Acute myeloid leukaemia with NPM1 mutation: Difference between revisions

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{{DISPLAYTITLE:Acute myeloid leukaemia with NPM1 mutation}}
{{DISPLAYTITLE:Acute myeloid leukaemia with NPM1 mutation}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
 
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
{{Under Construction}}


<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. The original page can be found at [[HAEM4:Acute Myeloid Leukemia (AML) with Mutated NPM1]].
<blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Acute Myeloid Leukemia (AML) with Mutated NPM1]].
}}</blockquote>
}}</blockquote>
==Primary Author(s)*==
Xinjie Xu, PhD, FACMG


__TOC__
<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>


==Cancer Category/Type==
==Primary Author(s)*==
<br />
==WHO Classification of Disease==


Acute Myeloid Leukemia (AML)
{| class="wikitable"
 
!Structure
==Cancer Sub-Classification / Subtype==
!Disease
 
|-
Acute myeloid leukaemia (AML) with mutated NPM1
|Book
 
|Haematolymphoid Tumours (5th ed.)
==Definition / Description of Disease==
|-
 
|Category
NPM1 mutated AML is a distinct disease entity in the 2016 World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia.
|Myeloid proliferations and neoplasms
 
|-
==Synonyms / Terminology==
|Family
 
|Acute myeloid leukaemia
AML with cytoplasmic nucleophosmin
|-
 
|Type
==Epidemiology / Prevalence==
|Acute myeloid leukaemia with defining genetic abnormalities
Somatic mutations of ''NPM1'' are observed in 22-18% of patients with ''de novo'' acute myeloid leukemia (AML), with a higher incidence (50-60%) in cytogenetically normal AML, making them one of the most frequent genetic alterations in AML<ref>{{Cite journal|last=Courville|first=Elizabeth L.|last2=Wu|first2=Yue|last3=Kourda|first3=Jihen|last4=Roth|first4=Christine G.|last5=Brockmann|first5=Jillian|last6=Muzikansky|first6=Alona|last7=Fathi|first7=Amir T.|last8=de Leval|first8=Laurence|last9=Orazi|first9=Attilio|date=2013|title=Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23307061|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=26|issue=6|pages=751–761|doi=10.1038/modpathol.2012.218|issn=1530-0285|pmid=23307061}}</ref><ref name=":0">{{Cite journal|last=Falini|first=Brunangelo|last2=Sportoletti|first2=Paolo|last3=Martelli|first3=Maria Paola|date=2009|title=Acute myeloid leukemia with mutated NPM1: diagnosis, prognosis and therapeutic perspectives|url=https://www.ncbi.nlm.nih.gov/pubmed/19770764|journal=Current Opinion in Oncology|volume=21|issue=6|pages=573–581|doi=10.1097/CCO.0b013e3283313dfa|issn=1531-703X|pmid=19770764}}</ref><ref name=":1">{{Cite journal|last=Papaemmanuil|first=Elli|last2=Gerstung|first2=Moritz|last3=Bullinger|first3=Lars|last4=Gaidzik|first4=Verena I.|last5=Paschka|first5=Peter|last6=Roberts|first6=Nicola D.|last7=Potter|first7=Nicola E.|last8=Heuser|first8=Michael|last9=Thol|first9=Felicitas|date=2016|title=Genomic Classification and Prognosis in Acute Myeloid Leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27276561|journal=The New England Journal of Medicine|volume=374|issue=23|pages=2209–2221|doi=10.1056/NEJMoa1516192|issn=1533-4406|pmc=4979995|pmid=27276561}}</ref>.
|-
 
|Subtype(s)
The incidence of mutated ''NPM1'' is much lower in other myeloid malignancies (5-6% of patients with chronic myelomonocytic leukemia and 2-5% of patients with myelodysplastic syndrome), however, it appears to increase after leukemic transformation (17% of CMML patients that progressed to AML and 9% of MDS-AML patients)<ref>{{Cite journal|last=Bains|first=Ashish|last2=Luthra|first2=Rajyalakshmi|last3=Medeiros|first3=L. Jeffrey|last4=Zuo|first4=Zhuang|date=2011|title=FLT3 and NPM1 mutations in myelodysplastic syndromes: Frequency and potential value for predicting progression to acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/21173125|journal=American Journal of Clinical Pathology|volume=135|issue=1|pages=62–69|doi=10.1309/AJCPEI9XU8PYBCIO|issn=1943-7722|pmid=21173125}}</ref><ref>{{Cite journal|last=Caudill|first=Jonathan S. C.|last2=Sternberg|first2=Alexander J.|last3=Li|first3=Chin-Yang|last4=Tefferi|first4=Ayalew|last5=Lasho|first5=Terra L.|last6=Steensma|first6=David P.|date=2006|title=C-terminal nucleophosmin mutations are uncommon in chronic myeloid disorders|url=https://www.ncbi.nlm.nih.gov/pubmed/16704439|journal=British Journal of Haematology|volume=133|issue=6|pages=638–641|doi=10.1111/j.1365-2141.2006.06081.x|issn=0007-1048|pmid=16704439}}</ref><ref>{{Cite journal|last=Dicker|first=F.|last2=Haferlach|first2=C.|last3=Sundermann|first3=J.|last4=Wendland|first4=N.|last5=Weiss|first5=T.|last6=Kern|first6=W.|last7=Haferlach|first7=T.|last8=Schnittger|first8=S.|date=2010|title=Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML|url=https://www.ncbi.nlm.nih.gov/pubmed/20520634|journal=Leukemia|volume=24|issue=8|pages=1528–1532|doi=10.1038/leu.2010.124|issn=1476-5551|pmid=20520634}}</ref><ref>{{Cite journal|last=Ernst|first=Thomas|last2=Chase|first2=Andrew|last3=Zoi|first3=Katerina|last4=Waghorn|first4=Katherine|last5=Hidalgo-Curtis|first5=Claire|last6=Score|first6=Joannah|last7=Jones|first7=Amy|last8=Grand|first8=Francis|last9=Reiter|first9=Andreas|date=2010|title=Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms|url=https://www.ncbi.nlm.nih.gov/pubmed/20421268|journal=Haematologica|volume=95|issue=9|pages=1473–1480|doi=10.3324/haematol.2010.021808|issn=1592-8721|pmc=2930947|pmid=20421268}}</ref><ref>{{Cite journal|last=Zhang|first=Yue|last2=Zhang|first2=Meirong|last3=Yang|first3=Lin|last4=Xiao|first4=Zhijian|date=2007|title=NPM1 mutations in myelodysplastic syndromes and acute myeloid leukemia with normal karyotype|url=https://www.ncbi.nlm.nih.gov/pubmed/16678898|journal=Leukemia Research|volume=31|issue=1|pages=109–111|doi=10.1016/j.leukres.2006.03.013|issn=0145-2126|pmid=16678898}}</ref>.
|Acute myeloid leukaemia with NPM1 mutation
 
|}
More common in females


==Clinical Features==
==Related Terminology==


Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|Acceptable
 
|N/A
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|EXAMPLE Cytopenias
|Myelodysplastic neoplasm with NPM1 mutation; myelodysplastic/myeloproliferative neoplasm with NPM1 mutation
 
EXAMPLE Lymphocytosis (low level)
|}
|}


==Gene Rearrangements==


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
Anemia, thrombocytopenia, high white blood cell and platelet counts
</blockquote>
==Sites of Involvement==


Bone marrow, gingiva, lymph nodes and skin
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>
 
==Morphologic Features==
 
Strong association with [[acute myelomonocytic]] and [[monocytic leukemia]] wich often have NPM1 nutations.
 
NPM1 mutations are also found in in AML with or without maturation and in pure erythroid leukemia.
 
==Immunophenotype==
 
POSITIVE:High CD33, low CD13, KIT,CD123,CD110
NEGATIVE: HLA-DR
 
IHC detection of cytoplasmic NPM1 expression is predictive on molecular mutation, because the morphological changes/staining are the result of the mutation effects in the cells.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!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
|-
|-
|Positive (universal)||EXAMPLE CD1
|<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).
|-
|-
|Positive (subset)||EXAMPLE CD2
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|Negative (universal)||EXAMPLE CD3
|<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).
|-
|-
|Negative (subset)||EXAMPLE CD4
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|}
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''


==Chromosomal Rearrangements (Gene Fusions)==


Put your text here and fill in the table
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>


{| class="wikitable sortable"
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
!Diagnostic Significance (Yes, No or Unknown)
|<span class="blue-text">EXAMPLE:</span> N/A
!Prognostic Significance (Yes, No or Unknown)
|<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.
!Therapeutic Significance (Yes, No or Unknown)
|<span class="blue-text">EXAMPLE:</span> N/A
!Notes
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|-
|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).
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>


Rare gene fusions involving ''NPM1'' genes (NPM1-MLF1 and NPM1–HAUS1) have been reported in patients with AML and are associated with cytoplasmic accumulation of NPM1<ref name=":2">{{Cite journal|last=Woolthuis|first=Carolien M.|last2=Mulder|first2=André B.|last3=Verkaik-Schakel|first3=Rikst Nynke|last4=Rosati|first4=Stefano|last5=Diepstra|first5=Arjan|last6=van den Berg|first6=Eva|last7=Schuringa|first7=Jan Jacob|last8=Vellenga|first8=Edo|last9=Kluin|first9=Philip M.|date=2013|title=A single center analysis of nucleophosmin in acute myeloid leukemia: value of combining immunohistochemistry with molecular mutation analysis|url=https://www.ncbi.nlm.nih.gov/pubmed/23716555|journal=Haematologica|volume=98|issue=10|pages=1532–1538|doi=10.3324/haematol.2012.079806|issn=1592-8721|pmc=3789457|pmid=23716555}}</ref><ref>{{Cite journal|last=Campregher|first=Paulo Vidal|last2=de Oliveira Pereira|first2=Welbert|last3=Lisboa|first3=Bianca|last4=Puga|first4=Renato|last5=Deolinda|first5=Elvira Rodrigues Pereira Velloso|last6=Helman|first6=Ricardo|last7=Marti|first7=Luciana Cavalheiro|last8=Guerra|first8=João Carlos Campos|last9=Manola|first9=Kalliopi N.|date=2016|title=A novel mechanism of NPM1 cytoplasmic localization in acute myeloid leukemia: the recurrent gene fusion NPM1-HAUS1|url=https://www.ncbi.nlm.nih.gov/pubmed/27036161|journal=Haematologica|volume=101|issue=7|pages=e287–290|doi=10.3324/haematol.2015.137364|issn=1592-8721|pmc=5004474|pmid=27036161}}</ref><ref name=":3">{{Cite journal|last=Falini|first=B.|last2=Bigerna|first2=B.|last3=Pucciarini|first3=A.|last4=Tiacci|first4=E.|last5=Mecucci|first5=C.|last6=Morris|first6=S. W.|last7=Bolli|first7=N.|last8=Rosati|first8=R.|last9=Hanissian|first9=S.|date=2006|title=Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML|url=https://www.ncbi.nlm.nih.gov/pubmed/16341033|journal=Leukemia|volume=20|issue=2|pages=368–371|doi=10.1038/sj.leu.2404068|issn=0887-6924|pmid=16341033}}</ref>.
Rare gene fusions involving ''NPM1'' genes (NPM1-MLF1 and NPM1–HAUS1) have been reported in patients with AML and are associated with cytoplasmic accumulation of NPM1<ref name=":2">{{Cite journal|last=Woolthuis|first=Carolien M.|last2=Mulder|first2=André B.|last3=Verkaik-Schakel|first3=Rikst Nynke|last4=Rosati|first4=Stefano|last5=Diepstra|first5=Arjan|last6=van den Berg|first6=Eva|last7=Schuringa|first7=Jan Jacob|last8=Vellenga|first8=Edo|last9=Kluin|first9=Philip M.|date=2013|title=A single center analysis of nucleophosmin in acute myeloid leukemia: value of combining immunohistochemistry with molecular mutation analysis|url=https://www.ncbi.nlm.nih.gov/pubmed/23716555|journal=Haematologica|volume=98|issue=10|pages=1532–1538|doi=10.3324/haematol.2012.079806|issn=1592-8721|pmc=3789457|pmid=23716555}}</ref><ref>{{Cite journal|last=Campregher|first=Paulo Vidal|last2=de Oliveira Pereira|first2=Welbert|last3=Lisboa|first3=Bianca|last4=Puga|first4=Renato|last5=Deolinda|first5=Elvira Rodrigues Pereira Velloso|last6=Helman|first6=Ricardo|last7=Marti|first7=Luciana Cavalheiro|last8=Guerra|first8=João Carlos Campos|last9=Manola|first9=Kalliopi N.|date=2016|title=A novel mechanism of NPM1 cytoplasmic localization in acute myeloid leukemia: the recurrent gene fusion NPM1-HAUS1|url=https://www.ncbi.nlm.nih.gov/pubmed/27036161|journal=Haematologica|volume=101|issue=7|pages=e287–290|doi=10.3324/haematol.2015.137364|issn=1592-8721|pmc=5004474|pmid=27036161}}</ref><ref name=":3">{{Cite journal|last=Falini|first=B.|last2=Bigerna|first2=B.|last3=Pucciarini|first3=A.|last4=Tiacci|first4=E.|last5=Mecucci|first5=C.|last6=Morris|first6=S. W.|last7=Bolli|first7=N.|last8=Rosati|first8=R.|last9=Hanissian|first9=S.|date=2006|title=Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML|url=https://www.ncbi.nlm.nih.gov/pubmed/16341033|journal=Leukemia|volume=20|issue=2|pages=368–371|doi=10.1038/sj.leu.2404068|issn=0887-6924|pmid=16341033}}</ref>.
Line 118: Line 116:
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 5%
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 5%
|-
|-
|EXAMPLE t(8;21)(q22;q22)||EXAMPLE 5'RUNX1 / 3'RUNXT1||EXAMPLE der(8)||EXAMPLE 5%
|<span class="blue-text">EXAMPLE:</span> t(8;21)(q22;q22)||<span class="blue-text">EXAMPLE:</span> 5'RUNX1 / 3'RUNXT1||<span class="blue-text">EXAMPLE:</span> der(8)||<span class="blue-text">EXAMPLE:</span> 5%
|}
|}


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>




<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
* Gene Mutations (SNV/INDEL)}}</blockquote>


*Diagnosis based on identification of genetic lesion of NPM1 by immunohistochemical and /or molecular testing.
*Diagnosis based on identification of genetic lesion of NPM1 by immunohistochemical and /or molecular testing.


*Mutated ''NPM1'' is associated with a favorable prognosis in AML patients who do not have FLT3-internal tandem duplication (FLT3-ITD) mutations and with normal karyotype<ref name=":0" /><ref name=":1" /><ref>{{Cite journal|last=Schnittger|first=S.|last2=Bacher|first2=U.|last3=Kern|first3=W.|last4=Alpermann|first4=T.|last5=Haferlach|first5=C.|last6=Haferlach|first6=T.|date=2011|title=Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/21537333|journal=Leukemia|volume=25|issue=8|pages=1297–1304|doi=10.1038/leu.2011.97|issn=1476-5551|pmid=21537333}}</ref><ref name=":7">{{Cite journal|last=Schnittger|first=Susanne|last2=Kern|first2=Wolfgang|last3=Tschulik|first3=Claudia|last4=Weiss|first4=Tamara|last5=Dicker|first5=Frank|last6=Falini|first6=Brunangelo|last7=Haferlach|first7=Claudia|last8=Haferlach|first8=Torsten|date=2009|title=Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML|url=https://www.ncbi.nlm.nih.gov/pubmed/19587375|journal=Blood|volume=114|issue=11|pages=2220–2231|doi=10.1182/blood-2009-03-213389|issn=1528-0020|pmid=19587375}}</ref>. A more recent study found that ''NPM1''-positive/''FLT3''-ITD-negative genotype predicts favorable outcomes in AML patients younger than 65 years, but not in those older than 65 years<ref>{{Cite journal|last=Ostronoff|first=Fabiana|last2=Othus|first2=Megan|last3=Lazenby|first3=Michelle|last4=Estey|first4=Elihu|last5=Appelbaum|first5=Frederick R.|last6=Evans|first6=Anna|last7=Godwin|first7=John|last8=Gilkes|first8=Amanda|last9=Kopecky|first9=Kenneth J.|date=2015|title=Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report|url=https://www.ncbi.nlm.nih.gov/pubmed/25713434|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=33|issue=10|pages=1157–1164|doi=10.1200/JCO.2014.58.0571|issn=1527-7755|pmc=4372852|pmid=25713434}}</ref>. Besides ''FLT3''-ITD, the prognostic impact of ''NPM1'' mutations in AML can be modified by the presence of other concurrent mutations. In ''NPM1'' mutated AML, concurrent mutations have been found in ''DNMT3A'' (54%), ''NRAS'' (19%), ''TET2'' (16%) and ''PTPN11'' (15%)<ref name=":1" />. ''DNMT3A'' missense mutations predicted shorter overall survival and higher cumulative incidence of relapse when stratified by ''NPM1'' mutation status, whereas '''NRAS'' truncation mutations do not correlate with clinical outcome<ref>{{Cite journal|last=Gale|first=Rosemary E.|last2=Lamb|first2=Katarina|last3=Allen|first3=Christopher|last4=El-Sharkawi|first4=Dima|last5=Stowe|first5=Cassandra|last6=Jenkinson|first6=Sarah|last7=Tinsley|first7=Steven|last8=Dickson|first8=Glenda|last9=Burnett|first9=Alan K.|date=2015|title=Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/25964253|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=33|issue=18|pages=2072–2083|doi=10.1200/JCO.2014.59.2022|issn=1527-7755|pmid=25964253}}</ref>. ''NRAS'' codon Gly12 and Gly13 mutations predict better overall survival in AML patients with concurrent ''NPM1'' and ''DNMT3A'' mutations<ref name=":1" />.
*Mutated ''NPM1'' is associated with a favorable prognosis in AML patients who do not have FLT3-internal tandem duplication (FLT3-ITD) mutations and with normal karyotype<ref name=":0">{{Cite journal|last=Falini|first=Brunangelo|last2=Sportoletti|first2=Paolo|last3=Martelli|first3=Maria Paola|date=2009|title=Acute myeloid leukemia with mutated NPM1: diagnosis, prognosis and therapeutic perspectives|url=https://www.ncbi.nlm.nih.gov/pubmed/19770764|journal=Current Opinion in Oncology|volume=21|issue=6|pages=573–581|doi=10.1097/CCO.0b013e3283313dfa|issn=1531-703X|pmid=19770764}}</ref><ref name=":1">{{Cite journal|last=Papaemmanuil|first=Elli|last2=Gerstung|first2=Moritz|last3=Bullinger|first3=Lars|last4=Gaidzik|first4=Verena I.|last5=Paschka|first5=Peter|last6=Roberts|first6=Nicola D.|last7=Potter|first7=Nicola E.|last8=Heuser|first8=Michael|last9=Thol|first9=Felicitas|date=2016|title=Genomic Classification and Prognosis in Acute Myeloid Leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27276561|journal=The New England Journal of Medicine|volume=374|issue=23|pages=2209–2221|doi=10.1056/NEJMoa1516192|issn=1533-4406|pmc=4979995|pmid=27276561}}</ref><ref>{{Cite journal|last=Schnittger|first=S.|last2=Bacher|first2=U.|last3=Kern|first3=W.|last4=Alpermann|first4=T.|last5=Haferlach|first5=C.|last6=Haferlach|first6=T.|date=2011|title=Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/21537333|journal=Leukemia|volume=25|issue=8|pages=1297–1304|doi=10.1038/leu.2011.97|issn=1476-5551|pmid=21537333}}</ref><ref name=":7">{{Cite journal|last=Schnittger|first=Susanne|last2=Kern|first2=Wolfgang|last3=Tschulik|first3=Claudia|last4=Weiss|first4=Tamara|last5=Dicker|first5=Frank|last6=Falini|first6=Brunangelo|last7=Haferlach|first7=Claudia|last8=Haferlach|first8=Torsten|date=2009|title=Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML|url=https://www.ncbi.nlm.nih.gov/pubmed/19587375|journal=Blood|volume=114|issue=11|pages=2220–2231|doi=10.1182/blood-2009-03-213389|issn=1528-0020|pmid=19587375}}</ref>. A more recent study found that ''NPM1''-positive/''FLT3''-ITD-negative genotype predicts favorable outcomes in AML patients younger than 65 years, but not in those older than 65 years<ref>{{Cite journal|last=Ostronoff|first=Fabiana|last2=Othus|first2=Megan|last3=Lazenby|first3=Michelle|last4=Estey|first4=Elihu|last5=Appelbaum|first5=Frederick R.|last6=Evans|first6=Anna|last7=Godwin|first7=John|last8=Gilkes|first8=Amanda|last9=Kopecky|first9=Kenneth J.|date=2015|title=Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report|url=https://www.ncbi.nlm.nih.gov/pubmed/25713434|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=33|issue=10|pages=1157–1164|doi=10.1200/JCO.2014.58.0571|issn=1527-7755|pmc=4372852|pmid=25713434}}</ref>. Besides ''FLT3''-ITD, the prognostic impact of ''NPM1'' mutations in AML can be modified by the presence of other concurrent mutations. In ''NPM1'' mutated AML, concurrent mutations have been found in ''DNMT3A'' (54%), ''NRAS'' (19%), ''TET2'' (16%) and ''PTPN11'' (15%)<ref name=":1" />. ''DNMT3A'' missense mutations predicted shorter overall survival and higher cumulative incidence of relapse when stratified by ''NPM1'' mutation status, whereas '''NRAS'' truncation mutations do not correlate with clinical outcome<ref>{{Cite journal|last=Gale|first=Rosemary E.|last2=Lamb|first2=Katarina|last3=Allen|first3=Christopher|last4=El-Sharkawi|first4=Dima|last5=Stowe|first5=Cassandra|last6=Jenkinson|first6=Sarah|last7=Tinsley|first7=Steven|last8=Dickson|first8=Glenda|last9=Burnett|first9=Alan K.|date=2015|title=Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/25964253|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=33|issue=18|pages=2072–2083|doi=10.1200/JCO.2014.59.2022|issn=1527-7755|pmid=25964253}}</ref>. ''NRAS'' codon Gly12 and Gly13 mutations predict better overall survival in AML patients with concurrent ''NPM1'' and ''DNMT3A'' mutations<ref name=":1" />.


*Minimal residual disease (MRD) monitoring of AML patients after chemotherapy provides important prognostic information<ref>{{Cite journal|last=Grimwade|first=David|last2=Freeman|first2=Sylvie D.|date=2014|title=Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "prime time"?|url=https://www.ncbi.nlm.nih.gov/pubmed/25049280|journal=Blood|volume=124|issue=23|pages=3345–3355|doi=10.1182/blood-2014-05-577593|issn=1528-0020|pmid=25049280}}</ref><ref>{{Cite journal|last=Hourigan|first=Christopher S.|last2=Karp|first2=Judith E.|date=2013|title=Minimal residual disease in acute myeloid leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23799371|journal=Nature Reviews. Clinical Oncology|volume=10|issue=8|pages=460–471|doi=10.1038/nrclinonc.2013.100|issn=1759-4782|pmc=4163748|pmid=23799371}}</ref>. Because ''NPM1'' mutations are very stable over the course of disease, they are an excellent marker for monitoring minimal residual disease (MRD) for ''NPM1'' mutated AML patients<ref name=":3" /><ref>{{Cite journal|last=Falini|first=B.|last2=Bolli|first2=N.|last3=Liso|first3=A.|last4=Martelli|first4=M. P.|last5=Mannucci|first5=R.|last6=Pileri|first6=S.|last7=Nicoletti|first7=I.|date=2009|title=Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications|url=https://www.ncbi.nlm.nih.gov/pubmed/19516275|journal=Leukemia|volume=23|issue=10|pages=1731–1743|doi=10.1038/leu.2009.124|issn=1476-5551|pmid=19516275}}</ref>. Indeed, several studies have suggested that MRD accessed by ''NPM1'' mutation level using PCR-based methods is a strong independent predictor of higher relapse risk<ref name=":7" /><ref>{{Cite journal|last=Ivey|first=Adam|last2=Hills|first2=Robert K.|last3=Simpson|first3=Michael A.|last4=Jovanovic|first4=Jelena V.|last5=Gilkes|first5=Amanda|last6=Grech|first6=Angela|last7=Patel|first7=Yashma|last8=Bhudia|first8=Neesa|last9=Farah|first9=Hassan|date=2016|title=Assessment of Minimal Residual Disease in Standard-Risk AML|url=https://www.ncbi.nlm.nih.gov/pubmed/26789727|journal=The New England Journal of Medicine|volume=374|issue=5|pages=422–433|doi=10.1056/NEJMoa1507471|issn=1533-4406|pmid=26789727}}</ref>.
*Minimal residual disease (MRD) monitoring of AML patients after chemotherapy provides important prognostic information<ref>{{Cite journal|last=Grimwade|first=David|last2=Freeman|first2=Sylvie D.|date=2014|title=Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "prime time"?|url=https://www.ncbi.nlm.nih.gov/pubmed/25049280|journal=Blood|volume=124|issue=23|pages=3345–3355|doi=10.1182/blood-2014-05-577593|issn=1528-0020|pmid=25049280}}</ref><ref>{{Cite journal|last=Hourigan|first=Christopher S.|last2=Karp|first2=Judith E.|date=2013|title=Minimal residual disease in acute myeloid leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23799371|journal=Nature Reviews. Clinical Oncology|volume=10|issue=8|pages=460–471|doi=10.1038/nrclinonc.2013.100|issn=1759-4782|pmc=4163748|pmid=23799371}}</ref>. Because ''NPM1'' mutations are very stable over the course of disease, they are an excellent marker for monitoring minimal residual disease (MRD) for ''NPM1'' mutated AML patients<ref name=":3" /><ref>{{Cite journal|last=Falini|first=B.|last2=Bolli|first2=N.|last3=Liso|first3=A.|last4=Martelli|first4=M. P.|last5=Mannucci|first5=R.|last6=Pileri|first6=S.|last7=Nicoletti|first7=I.|date=2009|title=Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications|url=https://www.ncbi.nlm.nih.gov/pubmed/19516275|journal=Leukemia|volume=23|issue=10|pages=1731–1743|doi=10.1038/leu.2009.124|issn=1476-5551|pmid=19516275}}</ref>. Indeed, several studies have suggested that MRD accessed by ''NPM1'' mutation level using PCR-based methods is a strong independent predictor of higher relapse risk<ref name=":7" /><ref>{{Cite journal|last=Ivey|first=Adam|last2=Hills|first2=Robert K.|last3=Simpson|first3=Michael A.|last4=Jovanovic|first4=Jelena V.|last5=Gilkes|first5=Amanda|last6=Grech|first6=Angela|last7=Patel|first7=Yashma|last8=Bhudia|first8=Neesa|last9=Farah|first9=Hassan|date=2016|title=Assessment of Minimal Residual Disease in Standard-Risk AML|url=https://www.ncbi.nlm.nih.gov/pubmed/26789727|journal=The New England Journal of Medicine|volume=374|issue=5|pages=422–433|doi=10.1056/NEJMoa1507471|issn=1533-4406|pmid=26789727}}</ref>.


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</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>


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"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Prognostic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Therapeutic Significance (Yes, No or Unknown)
!Clinical Relevance Details/Other Notes
!Notes
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
7
7
|EXAMPLE Loss
|<span class="blue-text">EXAMPLE:</span> Loss
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
chr7
|Yes
|<span class="blue-text">EXAMPLE:</span>
|Yes
Unknown
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE
|<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 reference).
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).
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
8
8
|EXAMPLE Gain
|<span class="blue-text">EXAMPLE:</span> Gain
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
chr8
|No
|<span class="blue-text">EXAMPLE:</span>
|No
Unknown
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE
|
 
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add reference).
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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<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal or Other Global Mutational 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>


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"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
!Prevalence -
!Therapeutic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Notes
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
Co-deletion of 1p and 18q
Co-deletion of 1p and 18q
|Yes
|<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).
|No
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE:
|
 
|
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>
Microsatellite instability - hypermutated
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|
|
|
|
|
|
|}
|}


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<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>


trisomy 8, deletion 9q
trisomy 8, deletion 9q


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==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 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>


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"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!'''Diagnostic Significance (Yes, No or Unknown)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span>''EGFR''


EXAMPLE:
<br />
 
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
EGFR; Exon 20 mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
 
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
EXAMPLE: BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> T
|EXAMPLE: TSG
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|EXAMPLE: 20% (COSMIC)
|<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).
 
|-
EXAMPLE: 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|EXAMPLE: IDH1 R123H
<br />
|EXAMPLE: EGFR amplification
|<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
|
|
|-
|
|
|
|
|
|
|
|
|
|
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|}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.
<br />
|}
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=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}


*Studies investigating the methods by which ''NPM1'' mutations lead to leukemogenesis show that ''NPM1'' mutation alone is not sufficient to cause AML<ref name=":4">{{Cite journal|last=Heath|first=E. M.|last2=Chan|first2=S. M.|last3=Minden|first3=M. D.|last4=Murphy|first4=T.|last5=Shlush|first5=L. I.|last6=Schimmer|first6=A. D.|date=2017|title=Biological and clinical consequences of NPM1 mutations in AML|url=https://www.ncbi.nlm.nih.gov/pubmed/28111462|journal=Leukemia|volume=31|issue=4|pages=798–807|doi=10.1038/leu.2017.30|issn=1476-5551|pmid=28111462}}</ref>.
*Studies investigating the methods by which ''NPM1'' mutations lead to leukemogenesis show that ''NPM1'' mutation alone is not sufficient to cause AML<ref name=":4">{{Cite journal|last=Heath|first=E. M.|last2=Chan|first2=S. M.|last3=Minden|first3=M. D.|last4=Murphy|first4=T.|last5=Shlush|first5=L. I.|last6=Schimmer|first6=A. D.|date=2017|title=Biological and clinical consequences of NPM1 mutations in AML|url=https://www.ncbi.nlm.nih.gov/pubmed/28111462|journal=Leukemia|volume=31|issue=4|pages=798–807|doi=10.1038/leu.2017.30|issn=1476-5551|pmid=28111462}}</ref>.
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!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|-
|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%
|<span class="blue-text">EXAMPLE:</span> TP53||<span class="blue-text">EXAMPLE:</span> R273H||<span class="blue-text">EXAMPLE:</span> Tumor Suppressor||<span class="blue-text">EXAMPLE:</span> LOF||<span class="blue-text">EXAMPLE:</span> 20%
|}
|}
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|}
|}


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==


Put your text here
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: Can include references in the table.'')</span>
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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|EXAMPLE: MAPK signaling
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|EXAMPLE: Unregulated cell division
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|EXAMPLE:  Abnormal gene expression program
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|-
|
|
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
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*The NPM1 gene encodes nucleophosmin (NPM), which is a multifunctional protein that shuttles between the nucleus and the cytoplasm, and binds many partners in distinct cellular compartments. It is involved in many cellular processes including ribosome biogenesis, maintenance of genomic stability and regulation of cellular proliferation.
*The NPM1 gene encodes nucleophosmin (NPM), which is a multifunctional protein that shuttles between the nucleus and the cytoplasm, and binds many partners in distinct cellular compartments. It is involved in many cellular processes including ribosome biogenesis, maintenance of genomic stability and regulation of cellular proliferation.
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*Mutations in ''NPM1'' represent a distinct entity in the World Health Organization (WHO) classification and commonly indicate a better risk prognosis<ref name=":4" />. Predominantly, observed ''NPM1'' variants are sited in exon 12 and cause a frameshift in the C-terminal domain, affecting one or both of the key tryptophan residues in the domain. Such ''NPM1'' mutations result in a ‘functionally stronger’ nuclear export than nuclear import signal (compared to wild-type NPM1) and thus there is cytoplasmic localization of the protein – ‘cytoplasmic NPM1’ (NPM1c)<ref name=":4" /><ref name=":6" />.  See Figure 3 in <ref name=":4" />. NPM1c sequesters ARF to the cytoplasm; however, unlike the ARF-NPM1 complex in the nucleolus, NPM1c is unable to stabilize ARF in the cytoplasm and consequently ARF becomes unstable and degrades<ref>{{Cite journal|last=Colombo|first=Emanuela|last2=Martinelli|first2=Paola|last3=Zamponi|first3=Raffaella|last4=Shing|first4=Danielle C.|last5=Bonetti|first5=Paola|last6=Luzi|first6=Lucilla|last7=Volorio|first7=Sara|last8=Bernard|first8=Loris|last9=Pruneri|first9=Giancarlo|date=2006|title=Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant|url=https://www.ncbi.nlm.nih.gov/pubmed/16540653|journal=Cancer Research|volume=66|issue=6|pages=3044–3050|doi=10.1158/0008-5472.CAN-05-2378|issn=0008-5472|pmid=16540653}}</ref>. Without ARF, there is lack of MDM2 inhibition, leading to p53 inactivation by MDM2 and the loss of growth inhibition by p53<ref name=":4" />. In the context of ''NPM1'' mutations, NPM1 haploinsufficiency results in uncontrolled centrosome duplication and consequently supernumerary centrosomes (a potential mechanism for tumor development)<ref>{{Cite journal|last=Sportoletti|first=Paolo|last2=Grisendi|first2=Silvia|last3=Majid|first3=Samia M.|last4=Cheng|first4=Ke|last5=Clohessy|first5=John G.|last6=Viale|first6=Agnes|last7=Teruya-Feldstein|first7=Julie|last8=Pandolfi|first8=Pier Paolo|date=2008|title=Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse|url=https://www.ncbi.nlm.nih.gov/pubmed/18212245|journal=Blood|volume=111|issue=7|pages=3859–3862|doi=10.1182/blood-2007-06-098251|issn=0006-4971|pmc=2275037|pmid=18212245}}</ref>. The loss of NPM1 function leads to activation of Myc oncogene (increased oncogene levels), promoting growth and cell proliferation. As expected, in the cytoplasm, NPM1c inhibits caspase-6/-8, promoting growth<ref name=":4" />.
*Mutations in ''NPM1'' represent a distinct entity in the World Health Organization (WHO) classification and commonly indicate a better risk prognosis<ref name=":4" />. Predominantly, observed ''NPM1'' variants are sited in exon 12 and cause a frameshift in the C-terminal domain, affecting one or both of the key tryptophan residues in the domain. Such ''NPM1'' mutations result in a ‘functionally stronger’ nuclear export than nuclear import signal (compared to wild-type NPM1) and thus there is cytoplasmic localization of the protein – ‘cytoplasmic NPM1’ (NPM1c)<ref name=":4" /><ref name=":6" />.  See Figure 3 in <ref name=":4" />. NPM1c sequesters ARF to the cytoplasm; however, unlike the ARF-NPM1 complex in the nucleolus, NPM1c is unable to stabilize ARF in the cytoplasm and consequently ARF becomes unstable and degrades<ref>{{Cite journal|last=Colombo|first=Emanuela|last2=Martinelli|first2=Paola|last3=Zamponi|first3=Raffaella|last4=Shing|first4=Danielle C.|last5=Bonetti|first5=Paola|last6=Luzi|first6=Lucilla|last7=Volorio|first7=Sara|last8=Bernard|first8=Loris|last9=Pruneri|first9=Giancarlo|date=2006|title=Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant|url=https://www.ncbi.nlm.nih.gov/pubmed/16540653|journal=Cancer Research|volume=66|issue=6|pages=3044–3050|doi=10.1158/0008-5472.CAN-05-2378|issn=0008-5472|pmid=16540653}}</ref>. Without ARF, there is lack of MDM2 inhibition, leading to p53 inactivation by MDM2 and the loss of growth inhibition by p53<ref name=":4" />. In the context of ''NPM1'' mutations, NPM1 haploinsufficiency results in uncontrolled centrosome duplication and consequently supernumerary centrosomes (a potential mechanism for tumor development)<ref>{{Cite journal|last=Sportoletti|first=Paolo|last2=Grisendi|first2=Silvia|last3=Majid|first3=Samia M.|last4=Cheng|first4=Ke|last5=Clohessy|first5=John G.|last6=Viale|first6=Agnes|last7=Teruya-Feldstein|first7=Julie|last8=Pandolfi|first8=Pier Paolo|date=2008|title=Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse|url=https://www.ncbi.nlm.nih.gov/pubmed/18212245|journal=Blood|volume=111|issue=7|pages=3859–3862|doi=10.1182/blood-2007-06-098251|issn=0006-4971|pmc=2275037|pmid=18212245}}</ref>. The loss of NPM1 function leads to activation of Myc oncogene (increased oncogene levels), promoting growth and cell proliferation. As expected, in the cytoplasm, NPM1c inhibits caspase-6/-8, promoting growth<ref name=":4" />.


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


Put your text here


Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
==Familial Forms==
==Familial Forms==


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>
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==


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==References==
==References==
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(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />


'''
<br />


==Notes==
==Notes==
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Prior author(s):
Xinjie Xu, PhD, FACMG




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<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with NPM1 mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_NPM1_mutation</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with NPM1 mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_NPM1_mutation</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases A]]
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