Bailey.Glen: Created page with "==Primary Author(s)== Alexandria Avery, DO Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Myeloid Neoplasms/Acute myeloid leukemia *Myelodysplastic Syndrome ==C..."

2023-11-03T17:31:53Z

Created page with "==Primary Author(s)*== Alexandria Avery, DO Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== *Myeloid Neoplasms/Acute myeloid leukemia *Myelodysplastic Syndrome ==C..."

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==Primary Author(s)*==

Alexandria Avery, DO

Daynna J. Wolff, PhD

__TOC__

==Cancer Category/Type==

*Myeloid Neoplasms/Acute myeloid leukemia
*Myelodysplastic Syndrome

==Cancer Sub-Classification / Subtype==

*Acute Myeloid Leukemia (AML) with GATA2 germline mutation

==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>Peterson LC, et al., (2017). Myeloid neoplasms with germline predisposition in WHO 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 Editors. IARC Press: Lyon, France, p126-128.</ref>. Acute myeloid leukemia with GATA2 mutation is a rare inherited germline predisposition mutation. It is associated with multiple clinical features and rare genetic disorders including MonoMAC or DCML Syndrome, Emberger Syndrome, and familial myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). Other genes identified in the familial AML-MDS disease category include RUNX1 and CEBPA<ref name=":0">{{Cite journal|last=Gao|first=Juehua|last2=Gentzler|first2=Ryan D.|last3=Timms|first3=Andrew E.|last4=Horwitz|first4=Marshall S.|last5=Frankfurt|first5=Olga|last6=Altman|first6=Jessica K.|last7=Peterson|first7=LoAnn C.|date=2014|title=Heritable GATA2 mutations associated with familial AML-MDS: a case report and review of literature|url=https://www.ncbi.nlm.nih.gov/pubmed/24754962|journal=Journal of Hematology & Oncology|volume=7|pages=36|doi=10.1186/1756-8722-7-36|issn=1756-8722|pmc=4006458|pmid=24754962}}</ref><ref name=":1">''UpToDate'', https://www.uptodate.com/contents/familial-disorders-of-acute-leukemia-and-myelodysplastic-syndromes </ref>.

==Synonyms / Terminology==

*Familial acute myeloid leukemia-myelodysplastic syndrome<ref name=":0" />

==Epidemiology / Prevalence==

*Germline GATA 2 mutations are a rare cause of familial MDS and AML, but the prevalence of the disorder is unknown<ref name=":0" /><ref name=":1" /><ref name=":2">{{Cite journal|last=Hyde|first=R. Katherine|last2=Liu|first2=P. Paul|date=2011|title=GATA2 mutations lead to MDS and AML|url=https://www.ncbi.nlm.nih.gov/pubmed/21956389|journal=Nature Genetics|volume=43|issue=10|pages=926–927|doi=10.1038/ng.949|issn=1546-1718|pmid=21956389}}</ref>.
*In a small series of MDS-AML cases, GATA2 mutations were identified in 4 of 12 (33 percent) and 4 of 27 (15 percent) families<ref>{{Cite journal|last=Holme|first=Harriet|last2=Hossain|first2=Upal|last3=Kirwan|first3=Michael|last4=Walne|first4=Amanda|last5=Vulliamy|first5=Tom|last6=Dokal|first6=Inderjeet|date=2012|title=Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/22533337|journal=British Journal of Haematology|volume=158|issue=2|pages=242–248|doi=10.1111/j.1365-2141.2012.09136.x|issn=1365-2141|pmid=22533337}}</ref>.
*MDS/AML develops in approximately 70 percent of affected individuals at a median age of onset of 29 years (range 0.4 to 78 years)<ref>{{Cite journal|last=Micol|first=Jean-Baptiste|last2=Abdel-Wahab|first2=Omar|date=2014|title=Collaborating constitutive and somatic genetic events in myeloid malignancies: ASXL1 mutations in patients with germline GATA2 mutations|url=https://www.ncbi.nlm.nih.gov/pubmed/24497555|journal=Haematologica|volume=99|issue=2|pages=201–203|doi=10.3324/haematol.2013.101303|issn=1592-8721|pmc=3912947|pmid=24497555}}</ref>.

==Clinical Features==

*Hematologic parameters may be normal prior to the development of MDS -AML or may present with monocytopenia, lymphopenia, or less frequently neutropenia<ref name=":3">{{Cite journal|last=Hahn|first=Christopher N.|last2=Chong|first2=Chan-Eng|last3=Carmichael|first3=Catherine L.|last4=Wilkins|first4=Ella J.|last5=Brautigan|first5=Peter J.|last6=Li|first6=Xiao-Chun|last7=Babic|first7=Milena|last8=Lin|first8=Ming|last9=Carmagnac|first9=Amandine|date=2011|title=Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/21892162|journal=Nature Genetics|volume=43|issue=10|pages=1012–1017|doi=10.1038/ng.913|issn=1546-1718|pmc=3184204|pmid=21892162}}</ref><ref name=":4">{{Cite journal|last=Spinner|first=Michael A.|last2=Sanchez|first2=Lauren A.|last3=Hsu|first3=Amy P.|last4=Shaw|first4=Pamela A.|last5=Zerbe|first5=Christa S.|last6=Calvo|first6=Katherine R.|last7=Arthur|first7=Diane C.|last8=Gu|first8=Wenjuan|last9=Gould|first9=Christine M.|date=2014|title=GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity|url=https://www.ncbi.nlm.nih.gov/pubmed/24227816|journal=Blood|volume=123|issue=6|pages=809–821|doi=10.1182/blood-2013-07-515528|issn=1528-0020|pmc=3916876|pmid=24227816}}</ref><ref>{{Cite journal|last=Pasquet|first=Marlène|last2=Bellanné-Chantelot|first2=Christine|last3=Tavitian|first3=Suzanne|last4=Prade|first4=Naïs|last5=Beaupain|first5=Blandine|last6=Larochelle|first6=Olivier|last7=Petit|first7=Arnaud|last8=Rohrlich|first8=Pierre|last9=Ferrand|first9=Christophe|date=2013|title=High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23223431|journal=Blood|volume=121|issue=5|pages=822–829|doi=10.1182/blood-2012-08-447367|issn=1528-0020|pmc=3714670|pmid=23223431}}</ref>.
*Defects in the GATA2 gene have led to a variety of clinical phenotypes that are inherited as autosomal dominant disorders with reduced penetrance<ref name=":0" /><ref name=":2" />:

#Familial MDS-AML: Individuals can present without any hematopoietic or organ system manifestations prior to the development of MDS or AML<ref name=":0" /><ref name=":1" />.
#Emberger Syndrome: Patients present with primary lymphedema, sensorineural deafness, cutaneous warts, and low CD4/CD8 T cell ratio, along with a predisposition for MDS-AML<ref name=":0" /><ref>{{Cite journal|last=Ostergaard|first=Pia|last2=Simpson|first2=Michael A.|last3=Connell|first3=Fiona C.|last4=Steward|first4=Colin G.|last5=Brice|first5=Glen|last6=Woollard|first6=Wesley J.|last7=Dafou|first7=Dimitra|last8=Kilo|first8=Tatjana|last9=Smithson|first9=Sarah|date=2011|title=Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)|url=https://www.ncbi.nlm.nih.gov/pubmed/21892158|journal=Nature Genetics|volume=43|issue=10|pages=929–931|doi=10.1038/ng.923|issn=1546-1718|pmid=21892158}}</ref>.
#MonoMAC or DCML Syndrome : Complex immunodeficiency characterized by monocytopenia, B-cell and NK-cell lymphocytopenia, near absent natural killer cells, and increased susceptibility to mycobacterium or papilloma virus infections, pulmonary alveolar proteinosis, along with a predisposition for MDS-AML<ref name=":0" /><ref>{{Cite journal|last=Dickinson|first=Rachel Emma|last2=Griffin|first2=Helen|last3=Bigley|first3=Venetia|last4=Reynard|first4=Louise N.|last5=Hussain|first5=Rafiqul|last6=Haniffa|first6=Muzlifah|last7=Lakey|first7=Jeremy H.|last8=Rahman|first8=Thahira|last9=Wang|first9=Xiao-Nong|date=2011|title=Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency|url=https://www.ncbi.nlm.nih.gov/pubmed/21765025|journal=Blood|volume=118|issue=10|pages=2656–2658|doi=10.1182/blood-2011-06-360313|issn=1528-0020|pmc=5137783|pmid=21765025}}</ref><ref>{{Cite journal|last=Hsu|first=Amy P.|last2=Sampaio|first2=Elizabeth P.|last3=Khan|first3=Javed|last4=Calvo|first4=Katherine R.|last5=Lemieux|first5=Jacob E.|last6=Patel|first6=Smita Y.|last7=Frucht|first7=David M.|last8=Vinh|first8=Donald C.|last9=Auth|first9=Roger D.|date=2011|title=Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21670465|journal=Blood|volume=118|issue=10|pages=2653–2655|doi=10.1182/blood-2011-05-356352|issn=1528-0020|pmc=3172785|pmid=21670465}}</ref>.

==Sites of Involvement==

AML-MDS with GATA2 mutation affects the hematopoietic and lymphatic systems<ref name=":0" />.

==Morphologic Features==

This entity is based on a genetic predisposition. Morphological features would be specific to the disease the patient develops.

==Immunophenotype==

This germline genetic defect leads to a predisposition to myeloid malignancies. The immunophenotype would be specific for the disease that the patient develops.

==Chromosomal Rearrangements (Gene Fusions)==

Not applicable
==Characteristic Chromosomal Aberrations / Patterns==

*Chromosomal aberrations would be specific for the disease that the patient develops. Common aberrations seen in MDS in these patients include typical anormalities: monosomy 7, trisomy 8, and trisomy 21<ref name=":0" /><ref name=":3" /><ref name=":4" /><ref name=":5">{{Cite journal|last=Fisher|first=Kevin E.|last2=Hsu|first2=Amy P.|last3=Williams|first3=Christopher L.|last4=Sayeed|first4=Hadi|last5=Merritt|first5=Brian Y.|last6=Elghetany|first6=M. Tarek|last7=Holland|first7=Steven M.|last8=Bertuch|first8=Alison A.|last9=Gramatges|first9=Maria Monica|date=2017|title=Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency|url=https://www.ncbi.nlm.nih.gov/pubmed/29296959|journal=Blood Advances|volume=1|issue=7|pages=443–448|doi=10.1182/bloodadvances.2016002311|issn=2473-9529|pmc=5738979|pmid=29296959}}</ref><ref name=":6">{{Cite journal|last=Wlodarski|first=Marcin W.|last2=Hirabayashi|first2=Shinsuke|last3=Pastor|first3=Victor|last4=Starý|first4=Jan|last5=Hasle|first5=Henrik|last6=Masetti|first6=Riccardo|last7=Dworzak|first7=Michael|last8=Schmugge|first8=Markus|last9=van den Heuvel-Eibrink|first9=Marry|date=2016|title=Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents|url=https://www.ncbi.nlm.nih.gov/pubmed/26702063|journal=Blood|volume=127|issue=11|pages=1387–1397; quiz 1518|doi=10.1182/blood-2015-09-669937|issn=1528-0020|pmid=26702063}}</ref>.

==Genomic Gain/Loss/LOH==

These changes would be specific for the disease that the patient develops.
==Gene Mutations (SNV/INDEL)==

*Mutations described have marked heterogeneity, variability, and present throughout the GATA2 gene. The most common mutation identified is a missense mutation (Thr354Met); however, insertions, deletions, and single base substitutions have also been described<ref name=":0" />. Two major classes of mutations have been identified. The first being an N-terminal frameshift mutation that results in a nonfunctional protein lacking most of the C-terminal. The second includes mutations in GATA2’s first and second zinc fingers<ref name=":0" /><ref name=":2" />.

===Other Mutations===

*Mutations in ''ASXL1'' are frequently acquired at the time of malignant progression. As in sporadic disease with ''ASXL1'' mutation, these mutations have a poor prognosis in germline mutation carriers<ref>{{Cite journal|last=West|first=Robert R.|last2=Hsu|first2=Amy P.|last3=Holland|first3=Steven M.|last4=Cuellar-Rodriguez|first4=Jennifer|last5=Hickstein|first5=Dennis D.|date=2014|title=Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation|url=https://www.ncbi.nlm.nih.gov/pubmed/24077845|journal=Haematologica|volume=99|issue=2|pages=276–281|doi=10.3324/haematol.2013.090217|issn=1592-8721|pmc=3912957|pmid=24077845}}</ref><ref>{{Cite journal|last=Bödör|first=Csaba|last2=Renneville|first2=Aline|last3=Smith|first3=Matthew|last4=Charazac|first4=Aurélie|last5=Iqbal|first5=Sameena|last6=Etancelin|first6=Pascaline|last7=Cavenagh|first7=Jamie|last8=Barnett|first8=Michael J.|last9=Kramarzová|first9=Karolina|date=2012|title=Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival|url=https://www.ncbi.nlm.nih.gov/pubmed/22271902|journal=Haematologica|volume=97|issue=6|pages=890–894|doi=10.3324/haematol.2011.054361|issn=1592-8721|pmc=3366655|pmid=22271902}}</ref>.

==Epigenomics (Methylation)==

==Genes and Main Pathways Involved==

*Monoallelic mutations in ''GATA2'', located on chromosome band 3q21.3<ref name=":3" />
*The GATA2 gene codes for a transcription factor that is involved in hematopoietic differentiation and lymphatic formation<ref name=":0" />.
*GATA2 is probably an important predisposing mutation but secondary genetic events are required for the development of overt malignant disease<ref name=":0" />.

==Diagnostic Testing Methods==

*Diagnosis of a familial AL/MDS syndrome is based on detection of the causal genetic abnormality in germline tissue (''i.e.'', non-hematologic cells)<ref name=":1" />.
*Recommended diagnostic testing includes ''GATA2'' exon sequencing, intron 5 enhancer region sequencing, and gene rearrangement testing<ref name=":1" />.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

*There is no agreed-upon protocol for optimal management of individuals diagnosed with a familial AL/MDS syndrome. The schedule and nature of monitoring must be individualized<ref name=":1" />.
*The high incidence of MDS/AML in these individuals warrants close monitoring for any signs or symptoms of these malignancies<ref name=":1" />.
*Allogeneic HCT has been successfully performed for a number of individuals with this syndrome<ref name=":4" /><ref>{{Cite journal|last=Cuellar-Rodriguez|first=Jennifer|last2=Gea-Banacloche|first2=Juan|last3=Freeman|first3=Alexandra F.|last4=Hsu|first4=Amy P.|last5=Zerbe|first5=Christa S.|last6=Calvo|first6=Katherine R.|last7=Wilder|first7=Jennifer|last8=Kurlander|first8=Roger|last9=Olivier|first9=Kenneth N.|date=2011|title=Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency|url=https://www.ncbi.nlm.nih.gov/pubmed/21816832|journal=Blood|volume=118|issue=13|pages=3715–3720|doi=10.1182/blood-2011-06-365049|issn=1528-0020|pmc=3186343|pmid=21816832}}</ref> and is the subject of an ongoing clinical trial (NCT01861106).
*HLA-matched relatives should be screened for the familial mutation and those carrying the mutation should be avoided<ref name=":1" />.

==Familial Forms==

*MonoMAC Syndrome
*Emberger Syndrome
*Familial AML-MDS

==Other Information==

Put your text here

==Links==

[[GATA2]]

'''[https://clinicaltrials.gov/ct2/show/NCT01861106?term=GATA2 Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Mutations]'''

==References==
<references />

==Notes==
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HAEM4Backup:Myeloid Neoplasms with Germline GATA2 Mutation - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Alexandria Avery, DO Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== *Myeloid Neoplasms/Acute myeloid leukemia *Myelodysplastic Syndrome ==C..."

Bailey.Glen: Created page with "==Primary Author(s)== Alexandria Avery, DO Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Myeloid Neoplasms/Acute myeloid leukemia *Myelodysplastic Syndrome ==C..."