View source for HAEM4:Myeloid Neoplasms with Germline DDX41 Mutation

{{DISPLAYTITLE:Myeloid Neoplasms with Germline DDX41 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)*==

Fei Yang, MD, FACMG

Oregon Health & Science University, Portland, OR

__TOC__

==Cancer Category/Type==

Myeloid Neoplasms with Germline Predisposition

==Cancer Sub-Classification / Subtype==

Myeloid Neoplasms with Germline ''DDX41'' 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 name=":0">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, p125.</ref>.

This entity defines cases of myeloid neoplasms, in particular MDS and AML, occur in association with inherited or ''de novo'' germline mutations in the ''DDX41'' gene.

==Synonyms / Terminology==

Familial myeloid neoplasms with germline ''DDX41'' mutation; familial myelodysplastic syndromes/acute leukemias with germline ''DDX41'' mutation

==Epidemiology / Prevalence==

Myeloid neoplasms with germline ''DDX41'' mutation usually have prolonged latency, with relatively old age at hematological malignancy onset similar to that of the sporadic cases of MDS or AML<ref name=":1">{{Cite journal|displayauthors=1|last=Sébert|first=Marie|last2=Passet|first2=Marie|last3=Raimbault|first3=Anna|last4=Rahmé|first4=Ramy|last5=Raffoux|first5=Emmanuel|last6=Sicre de Fontbrune|first6=Flore|last7=Cerrano|first7=Marco|last8=Quentin|first8=Samuel|last9=Vasquez|first9=Nadia|date=2019|title=Germline DDX41 mutations define a significant entity within adult MDS/AML patients|url=https://pubmed.ncbi.nlm.nih.gov/31484648|journal=Blood|volume=134|issue=17|pages=1441–1444|doi=10.1182/blood.2019000909|issn=1528-0020|pmid=31484648|via=}}</ref>. Males appear to be predominantly affected. The prevalence of ''DDX41''-related myeloid neoplasms has not been established. It was initially reported in 3-5% of pedigrees with suspected inherited hematological malignancies or familial MDS/AML<ref name=":2">{{Cite journal|displayauthors=1|last=Cardoso|first=S. R.|last2=Ryan|first2=G.|last3=Walne|first3=A. J.|last4=Ellison|first4=A.|last5=Lowe|first5=R.|last6=Tummala|first6=H.|last7=Rio-Machin|first7=A.|last8=Collopy|first8=L.|last9=Al Seraihi|first9=A.|date=2016|title=Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/27133828|journal=Leukemia|volume=30|issue=10|pages=2083–2086|doi=10.1038/leu.2016.124|issn=1476-5551|pmc=5008455|pmid=27133828|via=}}</ref><ref name=":3">{{Cite journal|displayauthors=1|last=Lewinsohn|first=Maya|last2=Brown|first2=Anna L.|last3=Weinel|first3=Luke M.|last4=Phung|first4=Connie|last5=Rafidi|first5=George|last6=Lee|first6=Ming K.|last7=Schreiber|first7=Andreas W.|last8=Feng|first8=Jinghua|last9=Babic|first9=Milena|date=2016|title=Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies|url=https://pubmed.ncbi.nlm.nih.gov/26712909|journal=Blood|volume=127|issue=8|pages=1017–1023|doi=10.1182/blood-2015-10-676098|issn=1528-0020|pmc=4968341|pmid=26712909|via=}}</ref>. The most recent study reported an incidence of 2.4% in an un-selected cohort of 1385 patients with MDS or AML<ref name=":1" />.

==Clinical Features==

The initial presentation is usually myeloid disorders without a pre-existing disorder or organ dysfunction. One large cohort study reported about half of the patients with germline ''DDX41''-related MDS/AML had a history of cytopenia several years before overt myeloid neoplasms<ref name=":1" />. Another recent study reported that ''DDX41'' germline mutations were detected in small fraction of individuals with Idiopathic cytopenia of undetermined significance (ICUS)<ref name=":5">Choi, Eun-Ji; et al. (2019). "''DDX41'' mutation in Patients with Idiopathic Cytopenia of Undetermined Significance, Myelodysplastic Syndrome, and Acute Myeloid Leukemia" ''Blood.'' '''134(Supplement_1)''':3002. https://doi.org/10.1182/blood-2019-129906.</ref>. Some mutations may also predispose to lymphoid malignancies<ref name=":1" /><ref name=":3" />. 

==Sites of Involvement==

Blood and bone marrow.

==Morphologic Features==

Patients with germline ''DDX41'' mutation who develop MDS/AML typically showed hypocellular bone marrow, significant neutropenia, and with prominent erythroid and megakaryocytic dysplasia<ref name=":0" /><ref name=":1" />. MDS is mainly MDS with multilineage dysplasia (MDS-MLD), MDS with excess blasts (MDS-EB), and MDS with isolated del(5q). AML is frequently present as the erythroblastic subtype (M6) by early report<ref name=":4">{{Cite journal|displayauthors=1|last=Polprasert|first=Chantana|last2=Schulze|first2=Isabell|last3=Sekeres|first3=Mikkael A.|last4=Makishima|first4=Hideki|last5=Przychodzen|first5=Bartlomiej|last6=Hosono|first6=Naoko|last7=Singh|first7=Jarnail|last8=Padgett|first8=Richard A.|last9=Gu|first9=Xiaorong|date=2015|title=Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/25920683|journal=Cancer Cell|volume=27|issue=5|pages=658–670|doi=10.1016/j.ccell.2015.03.017|issn=1878-3686|pmid=25920683|via=}}</ref>; however, another large cohort study identified subtypes M2, M1, and M0, without M6<ref name=":1" />.

==Immunophenotype==

No typical immunophenotype is described in the current literature.

==Chromosomal Rearrangements (Gene Fusions)==

No typical chromosomal rearrangements/gene fusions are described in the current literature.
==Characteristic Chromosomal Aberrations / Patterns==

Patients with germline ''DDX41'' mutation who develop MDS/AML usually present a normal karyotype, reported at 70-85%<ref name=":1" /><ref name=":4" /> . Other isolated chromosomal aberrations at low incidence include trisomy 8, deletion of 20q, and abnormalities involving chromosome 7<ref name=":1" /><ref name=":5" />.

==Genomic Gain/Loss/LOH==

Deletions of ''DDX41'' locus have been reported in 26% of MDS cases with del(5q)<ref name=":4" />.
==Gene Mutations (SNV/INDEL)==

The reported ''DDX41'' germline mutations include frameshift, missense, nonsense, and splicing mutations. The alterations commonly occur in the ATP binding domain, but could be anywhere throughout the gene. The most common mutations are p.D140Gfs*2 and p.M1I. Approximately half of cases had an acquired ''DDX41'' mutation affecting the remaining wild-type allele, with p.R525H as the most common somatic mutation<ref name=":1" /><ref name=":4" />.
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||''TP53, SF3B1, TET2, SMC3, NPM1, ASXL1, EZH2, DNMT3A, SRSF2, and other myeloid genes''
|-
|Secondary Mutations||
|-
|Mutually Exclusive||
|}

==Epigenomics (Methylation)==

Not applicable

==Genes and Main Pathways Involved==

The ''DDX41'' gene, located on the long arm of chromosome 5, encodes a DEAD-box RNA helicase. The Ddx41 protein has several major functional domains: DEAD/ATP binding domain, helicase C-terminal domain, and Zinc finger domain. The Ddx41 protein function and its molecular mechanism leading to hematologic malignancies remain elusive. It has been implicated to play roles in several cellular processes including innate immune response, mRNA splicing, and ribosome biogenesis, as well as to act as a tumor suppressor<ref name=":4" /><ref>{{Cite journal|displayauthors=1|last=Omura|first=Hiroki|last2=Oikawa|first2=Daisuke|last3=Nakane|first3=Takanori|last4=Kato|first4=Megumi|last5=Ishii|first5=Ryohei|last6=Ishitani|first6=Ryuichiro|last7=Tokunaga|first7=Fuminori|last8=Nureki|first8=Osamu|date=2016|title=Structural and Functional Analysis of DDX41: a bispecific immune receptor for DNA and cyclic dinucleotide|url=https://pubmed.ncbi.nlm.nih.gov/27721487|journal=Scientific Reports|volume=6|pages=34756|doi=10.1038/srep34756|issn=2045-2322|pmc=5056382|pmid=27721487|via=}}</ref>. In innate immunity, DDX41 activity regulates the STING-TBK1-IRF3 pathway in response to viral or bacterial infection<ref>{{Cite journal|displayauthors=1|last=Jiang|first=Yan|last2=Zhu|first2=Yanping|last3=Liu|first3=Zhi-Jie|last4=Ouyang|first4=Songying|date=2017|title=The emerging roles of the DDX41 protein in immunity and diseases|url=https://pubmed.ncbi.nlm.nih.gov/27502187|journal=Protein & Cell|volume=8|issue=2|pages=83–89|doi=10.1007/s13238-016-0303-4|issn=1674-8018|pmc=5291771|pmid=27502187|via=}}</ref>. 

==Diagnostic Testing Methods==

Myeloid gene panel testing by Next generation sequencing, PCR, Sanger sequencing

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

The prognosis of myeloid neoplasms with germline ''DDX41'' mutation is generally poor<ref name=":0" /><ref name=":4" />. Within the high-risk MDS/AML patients, the germline ''DDX41''-mutated patients have a better overall survive compared with the ''DDX41'' wild-type patients<ref name=":1" />. Early data have showed lenalidomide sensitivity in a limited number of patients with ''DDX41'' mutations<ref name=":4" />. 

==Familial Forms==

Myeloid neoplasms with germline ''DDX41'' mutation is a rare autosomal dominant disorder. Penetrance has not been well established. Asymptomatic carriers have been reported, suggesting variable penetrance<ref name=":2" /><ref name=":4" />. 

==Other Information==

Not applicable.

==Links==

''[[DDX41]]''

==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:HAEM4]] [[Category:DISEASE]]