Compendium of Cancer Genome Aberrations

HAEM5:Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion: Difference between revisions

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{{DISPLAYTITLE:Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion}}
{{DISPLAYTITLE:Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion}}
[[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 2023-11-30. The original page can be found at [[HAEM4:Acute Myeloid Leukemia (AML) with t(8;21)(q22;q22.1); RUNX1-RUNX1T1]].
<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 t(8;21)(q22;q22.1); RUNX1-RUNX1T1]].
}}</blockquote>
}}</blockquote>
<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)*==
Christine Bryke, MD<br>Beth Israel Deaconess Medical Center, Boston, MA
Christine Bryke, MD<br>Beth Israel Deaconess Medical Center, Boston, MA
==WHO Classification of Disease==


__TOC__
{| class="wikitable"
 
!Structure
==Cancer Category / Type==
!Disease
 
|-
Acute myeloid leukemia
|Book
 
|Haematolymphoid Tumours (5th ed.)
==Cancer Sub-Classification / Subtype==
|-
 
|Category
Acute myeloid leukaemia (AML) with t(8;21)(q22;q22.1) resulting in RUNX1-RUNX1T1 fusion
|Myeloid proliferations and neoplasms
 
|-
==Definition / Description of Disease==
|Family
 
|Acute myeloid leukaemia
Acute myeloid leukemia (AML) with t(8;21)(q22;q22) resulting in RUNX1-RUNX1T1 gene fusion defines a subtype of AML with neutrophil lineage maturation.  In the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, it is in the group of AML with recurrent genetic abnormalities<ref>{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert|last4=Thiele|first4=Jürgen|last5=Borowitz|first5=Michael J.|last6=Le Beau|first6=Michelle M.|last7=Bloomfield|first7=Clara D.|last8=Cazzola|first8=Mario|last9=Vardiman|first9=James W.|date=2016|title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27069254|journal=Blood|volume=127|issue=20|pages=2391–2405|doi=10.1182/blood-2016-03-643544|issn=1528-0020|pmid=27069254}}</ref>. In the older French-American-British (FAB) classification system, t(8;21)(q22;q22) positive AML belonged to the acute myeloblastic leukemia with maturation M2 category and accounted for 10% of cases.  t(8;21)(q22;q22) can occasionally be seen in therapy-related AML.  In those instances the leukemia is not classified in the group of AML with recurrent genetic abnormalities due to clinical and prognostic differences.  AML with t(8;21)(q22;q22) is a core binding leukemia (see Genes and Main Pathways Involved section below)<ref>{{Cite journal|last=Sangle|first=Nikhil A.|last2=Perkins|first2=Sherrie L.|date=2011|title=Core-binding factor acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/22032582|journal=Archives of Pathology & Laboratory Medicine|volume=135|issue=11|pages=1504–1509|doi=10.5858/arpa.2010-0482-RS|issn=1543-2165|pmid=22032582}}</ref>.
|-
 
|Type
*t(8;21)(q22;q22) is a translocation involving the long arms of chromosomes 8 and 21 that defines a distinctive cytogenetic subtype of [[AML|acute myeloid leukemia]].
|Acute myeloid leukaemia with defining genetic abnormalities
*Complex translocations involving chromosomes 8, 21 and a third chromosome occur; the derivative chromosome 8 in the t(8;21)(q22;q22) and the variant t(8;21;var) carries the RUNX1-RUNX1T1 gene rearrangement.
|-
*Cases with cryptic RUNX1-RUNX1T1 gene rearrangement have been reported.
|Subtype(s)
*Note: The RUNX1T1 gene is currently located at 8q21.3.  This gene was previously located at 8q22, which explains the discrepancy in the breakpoint given in the name for this WHO-defined disease entity.
|Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion
 
|}
<br>
==Related Terminology==
[[File:T_8_21_q22_q22.png|frame|center| Karyogram showing t(8;21)(q22;q22) translocation.  Jennifer
Otani, Beth Israel Deaconess Medical Center, Boston, MA]]
 
[[File:t(8;21)(q22;q22).png|frame|center| t(8;21)(q22;q22)]]
 
[[File:RUNX1_RUNXT1_FISH_Inverted.png|frame|center| FISH RUNX1-RUNX1T1 probe set on metaphase cell with
t(8;21)(q22;q22) translocation.  Jennifer Otani, Beth Israel
Deaconess Medical Center, Boston, MA.
]]
 
==Synonyms / Terminology==
 
AML1-ETO
 
==Epidemiology / Prevalence==


Approximately 1-5% of AML cases have the t(8;21)(q22;q22.1)
*Occurs mainly in younger patients
*Mean age is 30 years
*Most common type of AML in children
==Clinical Features==
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
 
|Acute myeloid leukaemia with t(8;21)(q22;q22.1)
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|EXAMPLE Cytopenias
|Acute myeloid leukaemia with AML1/ETO
 
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.}}
*May present as a myeloid sarcoma and, if so, the bone marrow aspirate blast count may be misleadingly low
*Concurrent systemic mastocytosis has been reported.
</blockquote>
==Sites of Involvement==
Bone marrow
==Morphologic Features==
*Large blasts with abundant basophilic cytoplasm often with azurophilic granules and perinuclear clearing
*Long sharp Auer rods are frequently observed.
<br>
[[File:AML_RUNX1_RUNXT1_Path.png|center|frame|Bone marrow aspirate with t(8;21)(q22;q22)
blast with Auer rod (100X).  Robert Willim, MD,
Beth Israel Deaconess Medical Center, Boston, MA]]
<br>
*Promyelocytes, myelocytes and metamyelocytes may have abnormal nuclear segmentation and cytoplasmic staining.
*Normal eosinophil precursors are frequently increased and do not show the nuclear and cytoplasmic abnormalities seen in AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22).
*Cases with t(8;21)(q22;q22.1) and less than 20% blast percentage in the marrow should be classified as AML rather than myelodysplastic  syndrome according to the WHO 2017<ref>Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France.</ref>.
==Immunophenotype==
*Blasts express CD34, HLA-DR, MPO, CD13, CD33 (weak), CD15 and/or CD65, co-expression of CD34. Lymphoid markers: CD19, PAX5, sometimes cytoplasmic CD79a
*Occasional weak TdT positivity and/or CD56 expression may have adverse prognosis


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>
{| 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)||CD34, HLA-DR, MPO, CD13, CD33 (weak), TdT (weak), CD56 (fraction of cases)
|<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)||CD15 and/or CD65
|<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).
|-
|-
|Positive (Lymphoid markers)
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|CD19, PAX5, sometimes cytoplasmic CD79a
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
|-
 
|Negative (universal)||
|-
|Negative (subset)||
|}<br />
==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
|
|
|
|}[[File:T_8_21_q22_q22.png|frame| Karyogram showing t(8;21)(q22;q22) translocation.  Jennifer
Otani, Beth Israel Deaconess Medical Center, Boston, MA|alt=|left]]


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).
[[File:t(8;21)(q22;q22).png|frame|center| t(8;21)(q22;q22)]]
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}
[[File:RUNX1_RUNXT1_FISH_Inverted.png|frame|center| FISH RUNX1-RUNX1T1 probe set on metaphase cell with
t(8;21)(q22;q22) translocation.  Jennifer Otani, Beth Israel
Deaconess Medical Center, Boston, MA.
]]
 
<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 151: Line 126:
|}
|}


<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>
Diagnostic:
Diagnostic:


Line 176: Line 154:
*Recently homoharringtonine, aclarubicin and cytarabine as the first course of induction therapy has been found to be highly effective for acute myeloid leukemia with t(8;21)(q22;q22)<ref name=":0" />.
*Recently homoharringtonine, aclarubicin and cytarabine as the first course of induction therapy has been found to be highly effective for acute myeloid leukemia with t(8;21)(q22;q22)<ref name=":0" />.


<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.
|-
|
|
|
|
|
|
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>


9q22 loss
9q22 loss


<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
|
|
|-
|
|
|
|
|
|
|}
|}


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


Additional aberrations in >70% of cases with t(8;21); common loss of a sex chromosome or deletion 9q
Additional aberrations in >70% of cases with t(8;21); common loss of a sex chromosome or deletion 9q


Trisomy 4 is a rare numerical abnormality detected in 3% of AML patients with t(8;21) (PMIDs: 12682630, 26573082, 27451976). A negative effect on prognosis this group of patients has been attributed to the presence of the mutations in the KIT gene.. Gain of chromosome 4 would likely result in increased dosage of the mutant KIT allele (PMIDs: 16291592, 30899636).
<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.
 


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


AML with t(8;21)(q22;q22) has genetic heterogeneity at the molecular level.  Several genes have been identified that are frequently mutated in this subset of AML, some of them adversely affecting prognosis.
AML with t(8;21)(q22;q22) has genetic heterogeneity at the molecular level.  Several genes have been identified that are frequently mutated in this subset of AML, some of them adversely affecting prognosis.
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|}
|}


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


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
 
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
|-
|-
|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
|-
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|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>


Genes:
Genes:
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*The normal transcriptional activity of the RUNX1 protein in the core binding factor is affected in a negative manner by the chimeric protein encoded by the RUNX1-RUNX1T1 fusion gene.  It has been proposed that the RUNX1-RUNX1T1 protein recruits histone deacetylases and DNA methyl transferase 1 to core binding factor target genes<ref>{{Cite journal|last=Marcucci|first=Guido|date=2006|title=Core binding factor acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/16728942|journal=Clinical Advances in Hematology & Oncology: H&O|volume=4|issue=5|pages=339–341|issn=1543-0790|pmid=16728942}}</ref>. This leads to increased chromatin deacetylation and promotor hypermethylation, resulting in gene transcriptional repression and disruption of normal cellular pathways of hematopoiesis.
*The normal transcriptional activity of the RUNX1 protein in the core binding factor is affected in a negative manner by the chimeric protein encoded by the RUNX1-RUNX1T1 fusion gene.  It has been proposed that the RUNX1-RUNX1T1 protein recruits histone deacetylases and DNA methyl transferase 1 to core binding factor target genes<ref>{{Cite journal|last=Marcucci|first=Guido|date=2006|title=Core binding factor acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/16728942|journal=Clinical Advances in Hematology & Oncology: H&O|volume=4|issue=5|pages=339–341|issn=1543-0790|pmid=16728942}}</ref>. This leads to increased chromatin deacetylation and promotor hypermethylation, resulting in gene transcriptional repression and disruption of normal cellular pathways of hematopoiesis.


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


None
This disease is <u>defined/characterized</u> as detailed below:
 
Acute myeloid leukemia (AML) with t(8;21)(q22;q22) resulting in RUNX1-RUNX1T1 gene fusion defines a subtype of AML with neutrophil lineage maturation.  In the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, it is in the group of AML with recurrent genetic abnormalities<ref>{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert|last4=Thiele|first4=Jürgen|last5=Borowitz|first5=Michael J.|last6=Le Beau|first6=Michelle M.|last7=Bloomfield|first7=Clara D.|last8=Cazzola|first8=Mario|last9=Vardiman|first9=James W.|date=2016|title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27069254|journal=Blood|volume=127|issue=20|pages=2391–2405|doi=10.1182/blood-2016-03-643544|issn=1528-0020|pmid=27069254}}</ref>. In the older French-American-British (FAB) classification system, t(8;21)(q22;q22) positive AML belonged to the acute myeloblastic leukemia with maturation M2 category and accounted for 10% of cases.  t(8;21)(q22;q22) can occasionally be seen in therapy-related AML.  In those instances the leukemia is not classified in the group of AML with recurrent genetic abnormalities due to clinical and prognostic differences.  AML with t(8;21)(q22;q22) is a core binding leukemia (see Genes and Main Pathways Involved section below)<ref>{{Cite journal|last=Sangle|first=Nikhil A.|last2=Perkins|first2=Sherrie L.|date=2011|title=Core-binding factor acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/22032582|journal=Archives of Pathology & Laboratory Medicine|volume=135|issue=11|pages=1504–1509|doi=10.5858/arpa.2010-0482-RS|issn=1543-2165|pmid=22032582}}</ref>.
 
*t(8;21)(q22;q22) is a translocation involving the long arms of chromosomes 8 and 21 that defines a distinctive cytogenetic subtype of [[AML|acute myeloid leukemia]].
*Complex translocations involving chromosomes 8, 21 and a third chromosome occur; the derivative chromosome 8 in the t(8;21)(q22;q22) and the variant t(8;21;var) carries the RUNX1-RUNX1T1 gene rearrangement.
*Cases with cryptic RUNX1-RUNX1T1 gene rearrangement have been reported.
*Note: The RUNX1T1 gene is currently located at 8q21.3.  This gene was previously located at 8q22, which explains the discrepancy in the breakpoint given in the name for this WHO-defined disease entity.
 
The <u>epidemiology/prevalence</u> of this disease is detailed below:
 
Approximately 1-5% of AML cases have the t(8;21)(q22;q22.1)
 
*Occurs mainly in younger patients
*Mean age is 30 years
*Most common type of AML in children
 
The <u>clinical features</u> of this disease are detailed below:
 
*May present as a myeloid sarcoma and, if so, the bone marrow aspirate blast count may be misleadingly low
*Concurrent systemic mastocytosis has been reported
 
The <u>sites of involvement</u> of this disease are detailed below:
 
*Bone marrow
 
The <u>morphologic features</u> of this disease are detailed below:
 
*Large blasts with abundant basophilic cytoplasm often with azurophilic granules and perinuclear clearing
*Long sharp Auer rods are frequently observed.
 
*Promyelocytes, myelocytes and metamyelocytes may have abnormal nuclear segmentation and cytoplasmic staining.
*Normal eosinophil precursors are frequently increased and do not show the nuclear and cytoplasmic abnormalities seen in AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22).
*Cases with t(8;21)(q22;q22.1) and less than 20% blast percentage in the marrow should be classified as AML rather than myelodysplastic syndrome according to the WHO 2017<ref>Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France.</ref>.
 
[[File:AML_RUNX1_RUNXT1_Path.png|center|frame|Bone marrow aspirate with t(8;21)(q22;q22)
blast with Auer rod (100X).  Robert Willim, MD,
Beth Israel Deaconess Medical Center, Boston, MA]]The <u>immunophenotype</u> of this disease is detailed below:
 
*Blasts express CD34, HLA-DR, MPO, CD13, CD33 (weak), CD15 and/or CD65, co-expression of CD34. Lymphoid markers: CD19, PAX5, sometimes cytoplasmic CD79a
*Occasional weak TdT positivity and/or CD56 expression may have adverse prognosis


==Links==
==Links==
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==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''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''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
(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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<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion”. 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_RUNX1::RUNX1T1_fusion</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion”. 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_RUNX1::RUNX1T1_fusion</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases A]]
Retrieved from "https://test.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_RUNX1::RUNX1T1_fusion"