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			{{DISPLAYTITLE:Acute Myeloid Leukaemia with Germline CEBPA Mutation}}


			<blockquote class='blockedit'>{{Box-round\|title=PREVIOUS EDITION\|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents\|Table of Contents]].
			}}</blockquote>
	==Primary Author(s)*==		==Primary Author(s)*==

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	==Notes==		==Notes==
	<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.		<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.
			[[Category:HAEM4]] [[Category:DISEASE]]
	[[Category:~~Cancer Genes C~~]]
	[[Category:~~Recently Added Pages~~]]

Bailey.Glen: Created page with "==Primary Author(s)*== Matthew Kilpatrick, MD and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Acute Myeloid Leukemia ==Cancer Sub-Classification / Subtype== Ac..."

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Created page with "==Primary Author(s)*== Matthew Kilpatrick, MD and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Acute Myeloid Leukemia ==Cancer Sub-Classification / Subtype== Ac..."

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==Primary Author(s)*==

Matthew Kilpatrick, MD and Daynna J. Wolff, PhD

__TOC__

==Cancer Category/Type==

Acute Myeloid Leukemia

==Cancer Sub-Classification / Subtype==

Acute Myeloid Leukemia (AML) with CEBPA germline mutations.

==Definition / Description of Disease==

This is a distinct entity in the World Health Organization (WHO) classification system within the section of [[Myeloid Neoplasms with Germline Predisposition]]<ref name=":6">Peterson LC, et al., (2017). Myeloid neoplasms with germline predisposition, 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, p124-125.</ref>.

Patients with germline CEBPA mutations have a rare inherited predisposition for acute myeloid leukemia. CEBPA mutation can occur as an acquired somatic mutation in sporadic AML or as a germline mutation that is inherited across multiple generations of affected family<ref name=":0">{{Cite journal|last=Gao|first=Juehua|last2=Gong|first2=Shunyou|last3=Chen|first3=Yi-Hua|date=2019|title=Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists|url=https://www.ncbi.nlm.nih.gov/pubmed/29372845|journal=Archives of Pathology & Laboratory Medicine|volume=143|issue=1|pages=13–22|doi=10.5858/arpa.2017-0194-RA|issn=1543-2165|pmid=29372845}}</ref>.

Families with germline CEBPA mutation typically inherit an N-terminal frameshift or nonsense mutation in one allele that predisposes to acquiring a somatic C-terminal CEBPA mutation on the other allele with high penetrance<ref name=":3">{{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|title=Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/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>. However, there a couple of reports of inheritance of a C-terminal germline variant with reduced penetrance <ref name=":4">{{Cite journal|last=Rio-Machin|first=Ana|last2=Vulliamy|first2=Tom|last3=Hug|first3=Nele|last4=Walne|first4=Amanda|last5=Tawana|first5=Kiran|last6=Cardoso|first6=Shirleny|last7=Ellison|first7=Alicia|last8=Pontikos|first8=Nikolas|last9=Wang|first9=Jun|date=2020|title=The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants|url=https://www.ncbi.nlm.nih.gov/pubmed/32098966|journal=Nature Communications|volume=11|issue=1|pages=1044|doi=10.1038/s41467-020-14829-5|issn=2041-1723|pmc=7042299|pmid=32098966}}</ref><ref name=":5">{{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|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://www.ncbi.nlm.nih.gov/pubmed/26721895|journal=Haematologica|volume=101|issue=7|pages=846–852|doi=10.3324/haematol.2015.130799|issn=1592-8721|pmc=5004464|pmid=26721895}}</ref>

==Synonyms / Terminology==
NA

==Epidemiology / Prevalence==

*Studies of large series of normal-karyotype AML have reported a frequency of CEBPA mutation of 8% to 13%; among these, 7% to 11% have germline CEBPA mutations.<ref name=":7">{{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|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://www.ncbi.nlm.nih.gov/pubmed/21177436|journal=Blood|volume=117|issue=8|pages=2469–2475|doi=10.1182/blood-2010-09-307280|issn=1528-0020|pmid=21177436}}</ref> <ref name=":8">{{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|title=Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/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>

*Average age of presentation is 24.5 years (1.75–46 years).<ref name=":1">{{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|title=Disease evolution and outcomes in familial AML with germline CEBPA mutations|url=https://www.ncbi.nlm.nih.gov/pubmed/26162409|journal=Blood|volume=126|issue=10|pages=1214–1223|doi=10.1182/blood-2015-05-647172|issn=1528-0020|pmid=26162409}}</ref>

==Clinical Features==

Familial and sporadic CEPBA -mutated cases share morphological and immunophenotypic features in common; therefore, patients with AML with germline CEBPA mutation may be indistinguishable from CEBPA-mutated sporadic AML, both clinically and by mutations.<ref name=":2">{{Cite journal|last=Czuchlewski|first=David R.|last2=Peterson|first2=LoAnn C.|date=2016-03|title=Myeloid Neoplasms with Germline Predisposition|url=http://dx.doi.org/10.1016/j.path.2015.09.010|journal=Surgical Pathology Clinics|volume=9|issue=1|pages=165–176|doi=10.1016/j.path.2015.09.010|issn=1875-9181}}</ref> Patients with familial AML with mutated CEBPA have an increased risk for AML relapse; however, the prognosis is favorable which is thought to be due to novel mutations that are not clonally related to the initial disease.<ref name=":1" /> Clinical features, age of onset of AML and family history can provide useful clues in identifying patients with germline CEBPA mutations, which are inherited in an autosomal dominant fashion and are highly penetrant.<ref name=":2" />

==Sites of Involvement==

*AML with CEBPA mutation affects the hematopoietic and lymphatic systems.

==Morphologic Features==

Morphologically, AML with mutated CEBPA often presents as AML with minimal differentiation or AML without maturation associated with normal karyotype. The blasts may show frequent Auer rods.<ref name=":0" />

==Immunophenotype==

The blasts in AML with germline CEBPA mutations often express aberrant CD7 by flow cytometry. <ref name=":0" />

==Chromosomal Rearrangements (Gene Fusions)==

NA
==Characteristic Chromosomal Aberrations / Patterns==

Often found in chromosomally normal AML.<ref name=":2" />

==Genomic Gain/Loss/LOH==

No typical pattern
==Gene Mutations (SNV/INDEL)==

The first germline mutation in CEBPA, an N-terminal (212delC) mutation that resulted in a 30-kDa protein with an alternative start site, leading to loss of a transactivation domain.<ref>{{Cite journal|last=Smith|first=Matthew L.|last2=Cavenagh|first2=Jamie D.|last3=Lister|first3=T. Andrew|last4=Fitzgibbon|first4=Jude|date=2004|title=Mutation of CEBPA in familial acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/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> Similar frameshift insertions and deletions at the N-terminus are the most common variants in families with AML with germline CEBPA.<ref name=":3" /><ref>{{Cite journal|last=Nanri|first=Tomoko|last2=Uike|first2=Naokuni|last3=Kawakita|first3=Toshiro|last4=Iwanaga|first4=Eisaku|last5=Mitsuya|first5=Hiroaki|last6=Asou|first6=Norio|date=2010|title=A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation|url=https://www.ncbi.nlm.nih.gov/pubmed/19953636|journal=Genes, Chromosomes & Cancer|volume=49|issue=3|pages=237–241|doi=10.1002/gcc.20734|issn=1098-2264|pmid=19953636}}</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|title=Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation|url=https://www.ncbi.nlm.nih.gov/pubmed/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=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|title=Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/15902292|journal=Leukemia|volume=19|issue=7|pages=1276–1278|doi=10.1038/sj.leu.2403788|issn=0887-6924|pmid=15902292}}</ref> In familial cases with germline CEBPA, typically a somatic C-terminal insertions or deletions is the second hit, suggesting that the AML was caused by biallelic CEBPA inactivation. Only a few cases have been reported to have a germline C-terminal mutations in CEBPA.<ref name=":4" /><ref name=":5" />
===Other Mutations===
==Epigenomics (Methylation)==
None at this time

==Genes and Main Pathways Involved==
The intron-less CEBPA gene encodes a protein that belongs to the basic region leucine zipper family of transcription factors that contains 2 transactivation domains, TAD1 and TAD2; a basic region mediating DNA binding; and a leucine zipper region (Zip) for dimerization. <ref>{{Cite journal|date=2019|title=CEBPA|url=https://en.wikipedia.org/w/index.php?title=CEBPA&oldid=905320736|journal=Wikipedia|language=en}}</ref>

==Diagnostic Testing Methods==
Diagnosis of AML with germline CEPBA mutations is based on detection of the causal genetic abnormality in germline tissue (ie, non-hematologic cells).

Evaluation of CEBPA mutation is required for any new AML with normal karyotype, as the 2016 World Health Organization classification recognizes AML with biallelic CEBPA mutation as a distinct entity of AML with recurrent genetic abnormalities. Clinical testing for the CEBPA gene is available either as a single gene assay or as part of gene panels. Because of the variations in the mutations, sequencing the entire CEBPA gene is recommended. If familial inheritance is suspected, additional testing for germline variant is recommended.<ref name=":6" /><ref name=":0" />

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
Acute myeloid leukemia patients with CEBPA mutations have a favorable clinical outcome, but the favorable outcome is limited to those with double mutations (mutations on each allele)<ref name=":7" /><ref name=":8" /><ref name=":1" />.

Concurrent FLT3 ITD, NPM1, or GATA2 mutations have also been reported and may indicate the heterogeneity in CEBPA mutated AML.<ref name=":7" /><ref>{{Cite journal|last=Preudhomme|first=Claude|last2=Sagot|first2=Christophe|last3=Boissel|first3=Nicolas|last4=Cayuela|first4=Jean-Michel|last5=Tigaud|first5=Isabelle|last6=de Botton|first6=Stéphane|last7=Thomas|first7=Xavier|last8=Raffoux|first8=Emmanuel|last9=Lamandin|first9=Charlotte|date=2002|title=Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA)|url=https://www.ncbi.nlm.nih.gov/pubmed/12351377|journal=Blood|volume=100|issue=8|pages=2717–2723|doi=10.1182/blood-2002-03-0990|issn=0006-4971|pmid=12351377}}</ref><ref>{{Cite journal|last=Green|first=Claire L.|last2=Tawana|first2=Kiran|last3=Hills|first3=Robert K.|last4=Bödör|first4=Csaba|last5=Fitzgibbon|first5=Jude|last6=Inglott|first6=Sarah|last7=Ancliff|first7=Phil|last8=Burnett|first8=Alan K.|last9=Linch|first9=David C.|date=2013|title=GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations|url=https://www.ncbi.nlm.nih.gov/pubmed/23560626|journal=British Journal of Haematology|volume=161|issue=5|pages=701–705|doi=10.1111/bjh.12317|issn=1365-2141|pmid=23560626}}</ref>

Individuals with germline CEBPA mutation–associated AML may recur with a different somatic CEBPA mutation, whereas in sporadic AML the CEBPA mutation appears stable throughout the disease course.<ref>{{Cite journal|last=Tiesmeier|first=Jens|last2=Czwalinna|first2=Andreas|last3=Müller-Tidow|first3=Carsten|last4=Krauter|first4=Jürgen|last5=Serve|first5=Hubert|last6=Heil|first6=Gerhard|last7=Ganser|first7=Arnold|last8=Verbeek|first8=Walter|date=2003|title=Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/14616999|journal=British Journal of Haematology|volume=123|issue=3|pages=413–419|doi=10.1046/j.1365-2141.2003.04618.x|issn=0007-1048|pmid=14616999}}</ref>

Although the recurrence is triggered by independent clones, the patients can still achieve a durable response to therapy and favorable long-term outcome.<ref name=":0" />

==Familial Forms==

==Other Information==

==Links==

Put your links here (use "Link" icon at top of page)

==References==
<references />

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

[[Category:Cancer Genes C]]
[[Category:Recently Added Pages]]

HAEM4:Acute Myeloid Leukaemia with Germline CEBPA Mutation - Revision history

Bailey.Glen at 18:43, 3 November 2023

Bailey.Glen: Created page with "==Primary Author(s)*== Matthew Kilpatrick, MD and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Acute Myeloid Leukemia ==Cancer Sub-Classification / Subtype== Ac..."

Bailey.Glen: Created page with "==Primary Author(s)*== Matthew Kilpatrick, MD and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Acute Myeloid Leukemia ==Cancer Sub-Classification / Subtype== Ac..."