Compendium of Cancer Genome Aberrations

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

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Patients with biallelic ''CEBPA'' mutations and a normal karyotype have a more favorable prognosis than those with monoallelic or no ''CEBPA'' mutations, with higher complete remission rates and longer disease-free survival, relapse-free survival, event-free survival, and overall survival<ref name=":0">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. Revised 4th Edition. IARC Press: Lyon, France, p142-144.</ref>.  
Patients with biallelic ''CEBPA'' mutations and a normal karyotype have a more favorable prognosis than those with monoallelic or no ''CEBPA'' mutations, with higher complete remission rates and longer disease-free survival, relapse-free survival, event-free survival, and overall survival<ref name=":0">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. Revised 4th Edition. IARC Press: Lyon, France, p142-144.</ref>.  
Patients with abnormal karyotypes (but not complex karyotypes) and biallelic ''CEBPA'' mutations also have longer disease-free survival, event-free survival, and overall survival when compared to patients with monoallelic or no ''CEBPA'' mutations<ref name=":0" />.
Patients with abnormal karyotypes (but not complex karyotypes) and biallelic ''CEBPA'' mutations also have longer disease-free survival, event-free survival, and overall survival when compared to patients with monoallelic or no ''CEBPA'' mutations<ref name=":0" />. Detection of bi''CEBPA'' should raise possibility of germline mutation. Approximately 5-10%  of bi''CEBPA'' AML cases have a germline N-terminal<ref>{{Cite journal|last=Taskesen|first=Erdogan|last2=Bullinger|first2=Lars|last3=Corbacioglu|first3=Andrea|last4=Sanders|first4=Mathijs A.|last5=Erpelinck|first5=Claudia A. J.|last6=Wouters|first6=Bas J.|last7=van der Poel-van de Luytgaarde|first7=Sonja C.|last8=Damm|first8=Frederik|last9=Krauter|first9=Jürgen|date=2011-02-24|title=Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity|url=https://pubmed.ncbi.nlm.nih.gov/21177436|journal=Blood|volume=117|issue=8|pages=2469–2475|doi=10.1182/blood-2010-09-307280|issn=1528-0020|pmid=21177436}}</ref>. In the familia from, AML has very high penetrance and presents relatively early (median aga: 245.5 years)<ref>{{Cite journal|last=Tawana|first=Kiran|last2=Wang|first2=Jun|last3=Renneville|first3=Aline|last4=Bödör|first4=Csaba|last5=Hills|first5=Robert|last6=Loveday|first6=Chey|last7=Savic|first7=Aleksandar|last8=Van Delft|first8=Frederik W.|last9=Treleaven|first9=Jennifer|date=2015-09-03|title=Disease evolution and outcomes in familial AML with germline CEBPA mutations|url=https://pubmed.ncbi.nlm.nih.gov/26162409|journal=Blood|volume=126|issue=10|pages=1214–1223|doi=10.1182/blood-2015-05-647172|issn=1528-0020|pmid=26162409}}</ref>. There are some notable familial AML-Associated ''CEBPA'' germline pathogenic variants: c.68delC, p.Pro23ArgfsTer137<ref>{{Cite journal|last=Smith|first=Matthew L.|last2=Cavenagh|first2=Jamie D.|last3=Lister|first3=T. Andrew|last4=Fitzgibbon|first4=Jude|date=2004-12-02|title=Mutation of CEBPA in familial acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/15575056|journal=The New England Journal of Medicine|volume=351|issue=23|pages=2403–2407|doi=10.1056/NEJMoa041331|issn=1533-4406|pmid=15575056}}</ref>; c.68dupC, p.His24AlafsTer84<ref>{{Cite journal|last=Sellick|first=G. S.|last2=Spendlove|first2=H. E.|last3=Catovsky|first3=D.|last4=Pritchard-Jones|first4=K.|last5=Houlston|first5=R. S.|date=2005-07|title=Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/15902292|journal=Leukemia|volume=19|issue=7|pages=1276–1278|doi=10.1038/sj.leu.2403788|issn=0887-6924|pmid=15902292}}</ref><ref>{{Cite journal|last=Renneville|first=A.|last2=Mialou|first2=V.|last3=Philippe|first3=N.|last4=Kagialis-Girard|first4=S.|last5=Biggio|first5=V.|last6=Zabot|first6=M.-T.|last7=Thomas|first7=X.|last8=Bertrand|first8=Y.|last9=Preudhomme|first9=C.|date=2009-04|title=Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation|url=https://pubmed.ncbi.nlm.nih.gov/18946494|journal=Leukemia|volume=23|issue=4|pages=804–806|doi=10.1038/leu.2008.294|issn=1476-5551|pmid=18946494}}</ref><ref>{{Cite journal|last=Tawana|first=Kiran|last2=Wang|first2=Jun|last3=Renneville|first3=Aline|last4=Bödör|first4=Csaba|last5=Hills|first5=Robert|last6=Loveday|first6=Chey|last7=Savic|first7=Aleksandar|last8=Van Delft|first8=Frederik W.|last9=Treleaven|first9=Jennifer|date=2015-09-03|title=Disease evolution and outcomes in familial AML with germline CEBPA mutations|url=https://pubmed.ncbi.nlm.nih.gov/26162409|journal=Blood|volume=126|issue=10|pages=1214–1223|doi=10.1182/blood-2015-05-647172|issn=1528-0020|pmid=26162409}}</ref>; c.141delC, p.Ala48ProfsTer112<ref name=":1">{{Cite journal|last=Pabst|first=Thomas|last2=Eyholzer|first2=Marianne|last3=Haefliger|first3=Simon|last4=Schardt|first4=Julian|last5=Mueller|first5=Beatrice U.|date=2008-11-01|title=Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/18768433|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=26|issue=31|pages=5088–5093|doi=10.1200/JCO.2008.16.5563|issn=1527-7755|pmid=18768433}}</ref>; c.147_165del19, p.Glu50AlafsTer104<ref>{{Cite journal|last=Debeljak|first=Maruša|last2=Kitanovski|first2=Lidija|last3=Pajič|first3=Tadej|last4=Jazbec|first4=Janez|date=2013-07|title=Concordant acute myeloblastic leukemia in monozygotic twins with germline and shared somatic mutations in the gene for CCAAT-enhancer-binding protein α with 13 years difference at onset|url=https://pubmed.ncbi.nlm.nih.gov/23716546|journal=Haematologica|volume=98|issue=7|pages=e73–74|doi=10.3324/haematol.2012.082578|issn=1592-8721|pmc=3696596|pmid=23716546}}</ref>; c.158delG, p.Gly53AlafsTer107<ref name=":4">{{Cite journal|last=Taskesen|first=Erdogan|last2=Bullinger|first2=Lars|last3=Corbacioglu|first3=Andrea|last4=Sanders|first4=Mathijs A.|last5=Erpelinck|first5=Claudia A. J.|last6=Wouters|first6=Bas J.|last7=van der Poel-van de Luytgaarde|first7=Sonja C.|last8=Damm|first8=Frederik|last9=Krauter|first9=Jürgen|date=2011-02-24|title=Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity|url=https://pubmed.ncbi.nlm.nih.gov/21177436|journal=Blood|volume=117|issue=8|pages=2469–2475|doi=10.1182/blood-2010-09-307280|issn=1528-0020|pmid=21177436}}</ref>; c.189delC, p.Asp63GlufsTer97<ref name=":4" />; c.314_315insT, p.Phe106LeufsTer2<ref name=":1" />; c.932A>C, p.Gln311Pro<ref>{{Cite journal|last=Pathak|first=Anand|last2=Seipel|first2=Katja|last3=Pemov|first3=Alexander|last4=Dewan|first4=Ramita|last5=Brown|first5=Christina|last6=Ravichandran|first6=Sarangan|last7=Luke|first7=Brian T.|last8=Malasky|first8=Michael|last9=Suman|first9=Shalabh|date=2016-07|title=Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family|url=https://pubmed.ncbi.nlm.nih.gov/26721895|journal=Haematologica|volume=101|issue=7|pages=846–852|doi=10.3324/haematol.2015.130799|issn=1592-8721|pmc=5004464|pmid=26721895}}</ref>; c.442G>T, p.Glu148Ter<ref>{{Cite journal|last=Mendoza|first=Hadrian|last2=Chen|first2=Po-Han|last3=Pine|first3=Alexander B.|last4=Siddon|first4=Alexa J.|last5=Bale|first5=Allen E.|last6=Gowda|first6=Lohith|last7=Killie|first7=Amy|last8=Richards|first8=Jonica|last9=Varin-Tremblay|first9=Camille|date=2021-05|title=A case of acute myeloid leukemia with unusual germline CEBPA mutation: lessons learned about mutation detection, location, and penetrance|url=https://pubmed.ncbi.nlm.nih.gov/33345654|journal=Leukemia & Lymphoma|volume=62|issue=5|pages=1251–1254|doi=10.1080/10428194.2020.1861276|issn=1029-2403|pmid=33345654}}</ref>.  


Pathogenic mutations in ''CEBPA'' are predominantly insertion/deletion frameshift mutations in the N-terminal TAD region and in-frame C-terminal bZIP mutations. No particular mutational hotspots exist but the following table records the most reported mutations in the COSMIC database (frequency based on a count out of 1523 mutations):
Pathogenic mutations in ''CEBPA'' are predominantly insertion/deletion frameshift mutations in the N-terminal TAD region and in-frame C-terminal bZIP mutations. Patients with biCEBPA and smbZIP-CEBPA are younger and have higher white blood cell counts than those with a single mutation in the N-terminal TAD region<ref name=":5">{{Cite journal|last=Taube|first=Franziska|last2=Georgi|first2=Julia Annabell|last3=Kramer|first3=Michael|last4=Stasik|first4=Sebastian|last5=Middeke|first5=Jan Moritz|last6=Röllig|first6=Christoph|last7=Krug|first7=Utz|last8=Krämer|first8=Alwin|last9=Scholl|first9=Sebastian|date=2022-01-06|title=CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome|url=https://pubmed.ncbi.nlm.nih.gov/34320176|journal=Blood|volume=139|issue=1|pages=87–103|doi=10.1182/blood.2020009680|issn=1528-0020|pmid=34320176}}</ref>. No particular mutational hotspots exist but the following table records the most reported mutations in the COSMIC database (frequency based on a count out of 1523 mutations):
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|c.939_940insAAG, p.K313_V314insK
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Recurrent (AML)
|<span class="blue-text">EXAMPLE:</span> T
|D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|AML with ''CEBPA'' mutation is associated with favorable prognosis<ref>{{Cite journal|displayauthors=1|last=Pollyea|first=DA|date=2025|title=NCCN Clinical Practice Guidelines in Oncology: AML.|url=NCCN.org|journal=NCCN|volume=|pages=|via=}}</ref>.
 
 
AML with CEBPA mutation constitutes ~5% pf pediatric AML and 5-11% adult AML<ref>{{Cite journal|last=Tarlock|first=Katherine|last2=Lamble|first2=Adam J.|last3=Wang|first3=Yi-Cheng|last4=Gerbing|first4=Robert B.|last5=Ries|first5=Rhonda E.|last6=Loken|first6=Michael R.|last7=Brodersen|first7=Lisa Eidenschink|last8=Pardo|first8=Laura|last9=Leonti|first9=Amanda|date=2021-09-30|title=CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group|url=https://pubmed.ncbi.nlm.nih.gov/33951732|journal=Blood|volume=138|issue=13|pages=1137–1147|doi=10.1182/blood.2020009652|issn=1528-0020|pmc=8570058|pmid=33951732}}</ref><ref>{{Cite journal|last=Wakita|first=Satoshi|last2=Sakaguchi|first2=Masahiro|last3=Oh|first3=Iekuni|last4=Kako|first4=Shinichi|last5=Toya|first5=Takashi|last6=Najima|first6=Yuho|last7=Doki|first7=Noriko|last8=Kanda|first8=Junya|last9=Kuroda|first9=Junya|date=2022-01-11|title=Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/34448807|journal=Blood Advances|volume=6|issue=1|pages=238–247|doi=10.1182/bloodadvances.2021004292|issn=2473-9537|pmc=8753195|pmid=34448807}}</ref><ref name=":5" />.
|-
|-
|''CEBPA''
|''CEBPA''
<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|c.68_69insC, p.H24fs*84
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|Recurrent (AML)
|<span class="blue-text">EXAMPLE:</span> P
|D, P, T
|Yes (NCCN)
|
|
|<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.
|-
|-
|''CEBPA''
|''CEBPA''
|c.247delC, p.Q83fs*77
|c.247delC, p.Q83fs*77
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Recurrent (AML)
|<span class="blue-text">EXAMPLE:</span> T
|D, P, T
|
|Yes (NCCN)
|
|
|-
|-
|''CEBPA''
|''CEBPA''
|c.936_937insCAG, p.Q312_K313insQ
|c.936_937insCAG, p.Q312_K313insQ
|Oncogene
|Recurrent (AML)
|D, P, T
|Yes (NCCN)
|
|
|-
|''CEBPA''
|c.912_913insTTG, p.K304_Q305insL
|Oncogene
|Recurrent (AML)
|D, P, T
|Yes (NCCN)
|
|
|-
|
|
|
|
|Oncogene
|Recurrent (AML)
|D, P, T
|Yes (NCCN)
|
|
|-
|-
|''CEBPA''
|
|c.912_913insTTG, p.K304_Q305insL
|
|Oncogene
|Recurrent (AML)
|D, P, T
|Yes (NCCN)
|
|-
|
|
|
|
|
|
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|
|
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|}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 />


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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.}}</blockquote>
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