U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-.

Cover of PDQ Cancer Information Summaries

PDQ Cancer Information Summaries [Internet].

Show details

DDX41-Associated Myeloid Malignancies (PDQ®)

Health Professional Version

.

Published online: December 14, 2023.

Created: .

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of DDX41-associated myeloid malignancies. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Introduction and Clinical Manifestations of DDX41-Associated Myeloid Malignancies

[Note: A concerted effort is being made within the genetics community to use the term, variant rather than the term, mutation to describe genetic differences in the germline. These variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term, pathogenic variant to describe a disease-causing mutation. In this summary, the term, somatic mutations will be used to describe acquired genetic changes that arise in the hematopoietic system (blood stem cells and blood progenitor cells). For more information about variant classification, see the Cancer Genetics Overview summary.]

Germline pathogenic variants in the RNA helicase, DDX41, are associated with an autosomal dominant predisposition to myeloid malignancies and other cancers. The prevalence of DDX41 germline pathogenic variants is not clearly defined. However, these variants are thought to underlie 1% to 1.5% of all acute myeloid leukemia (AML) diagnoses,[1] making it one of the most commonly inherited predispositions to adult-onset myeloid malignancies.[2] Individuals who inherit DDX41 pathogenic variants have an increased lifetime risk to develop myelodysplastic syndrome (MDS) and AML. However, lymphoid malignancies such as non-Hodgkin lymphoma and myeloproliferative neoplasm (MPN) have also been reported in individuals with DDX41 pathogenic variants.[3-5]

DDX41 germline pathogenic variants are associated with a later median age of MDS/AML diagnosis than other inherited hematologic predisposition syndromes.[6] For DDX41 carriers, the age of MDS/AML diagnosis can range from 61 to 69 years. This age range is similar to the typical age of diagnosis in patients with sporadic MDS/AML in the general population. The myeloid malignancies that occur in individuals with DDX41 germline pathogenic variants are almost always diploid and harbor lower somatic mutational burdens than those seen in individuals without DDX41 germline pathogenic variants.[4,6] The penetrance of DDX41 pathogenic variants is incomplete and variable. DDX41 pathogenic variants are associated with a mild to moderate predisposition to hematologic malignancies (lifetime risk of hematologic malignancies ranges from 20% to 30% in DDX41 carriers). Nearly half of reported DDX41 carriers develop long-standing asymptomatic cytopenias (most commonly leukopenia) prior to malignancy development. However, some DDX41 carriers will only ever develop stable cytopenias that never progress to become hematologic malignancies. In these cases, individuals are typically transfusion-independent.[2]

Since DDX41 pathogenic variants have low penetrance and DDX41-related hematologic malignancies are often diagnosed at later ages, DDX41 carriers can be difficult to identify using the typical age– or family history–related screening criteria.

References

  1. Polprasert C, Schulze I, Sekeres MA, et al.: Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 27 (5): 658-70, 2015. [PMC free article: PMC8713504] [PubMed: 25920683]
  2. Sébert M, Passet M, Raimbault A, et al.: Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood 134 (17): 1441-1444, 2019. [PubMed: 31484648]
  3. Lewinsohn M, Brown AL, Weinel LM, et al.: Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 127 (8): 1017-23, 2016. [PMC free article: PMC4968341] [PubMed: 26712909]
  4. Li P, Brown S, Williams M, et al.: The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms. Blood 140 (7): 716-755, 2022. [PMC free article: PMC9389629] [PubMed: 35671390]
  5. Goyal T, Tu ZJ, Wang Z, et al.: Clinical and Pathologic Spectrum of DDX41-Mutated Hematolymphoid Neoplasms. Am J Clin Pathol 156 (5): 829-838, 2021. [PubMed: 33929502]
  6. Quesada AE, Routbort MJ, DiNardo CD, et al.: DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am J Hematol 94 (7): 757-766, 2019. [PubMed: 30963592]

Genetics and Molecular Biology of DDX41-Associated Myeloid Malignancies

DDX41 somatic mutations occur in myeloid and lymphoid malignancies and are increasingly included as part of somatic next-generation sequencing (NGS) panels. Studies have shown that molecular profiling is a useful and feasible tool to screen patients with hematologic malignancies for germline DDX41 pathogenic variants.[1,2] Two common Northern European founder pathogenic variants, p.Asp140Glyfs*2 and p.Met1Ile, account for most DDX41 germline pathogenic variants identified in individuals with European ancestry. As genetic testing becomes more routine, testing in additional populations indicates that missense variants, like DDX41 p.Val152Gly (p.V152G) and DDX41 p.Tyr259Cys (p.Y259C), may be more common in non-European populations.[3] When these missense and founder variants are found on somatic testing, they are present in the germline nearly 100% of the time. However, multiple nonsense and frameshift germline variants have been reported throughout the DDX41 gene. Therefore, full DDX41 gene sequencing is indicated when evaluating for a germline pathogenic variant.

In nearly 80% of cases, a second, somatically-acquired mutation (often the DDX41 p.Arg525His [p.R525H] variant), is acquired on the other DDX41 allele. This second hit is associated with progression to hematologic malignancy.[4,5] Likewise, if the DDX41 p.Arg525His variant is detected on somatic testing, even in absence of an additional DDX41 variant (presumably on the other allele), germline testing is warranted. Germline pathogenic variants on the other DDX41 allele could be present, especially when full somatic sequencing of the gene is not performed.

References

  1. Sébert M, Passet M, Raimbault A, et al.: Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood 134 (17): 1441-1444, 2019. [PubMed: 31484648]
  2. Bannon SA, Routbort MJ, Montalban-Bravo G, et al.: Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations. Front Oncol 10: 582213, 2020. [PMC free article: PMC7878971] [PubMed: 33585199]
  3. Choi EJ, Cho YU, Hur EH, et al.: Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia. Haematologica 107 (2): 510-518, 2022. [PMC free article: PMC8804579] [PubMed: 33626862]
  4. Polprasert C, Schulze I, Sekeres MA, et al.: Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 27 (5): 658-70, 2015. [PMC free article: PMC8713504] [PubMed: 25920683]
  5. Duployez N, Largeaud L, Duchmann M, et al.: Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study. Blood 140 (7): 756-768, 2022. [PMC free article: PMC9389637] [PubMed: 35443031]

Management and Prognosis for DDX41-Associated Myeloid Malignancies

Emerging data suggest that DDX41 carriers who develop acute myeloid leukemia (AML) have higher complete remission rates and longer mean overall survival rates than individuals who do not carry a DDX41 pathogenic variant.[1-3] In addition, individuals with DDX41 germline pathogenic variants who develop myelodysplastic syndrome (MDS)/AML may show responses to treatment with lenalidomide.[3-6]

At least two cases of donor-derived leukemias have occurred in DDX41 carriers post–hematopoietic stem cell transplant (HSCT) from a matched-related donor carrying the same germline DDX41 pathogenic variant.[7,8] This highlights the need for systematic screening of germline DDX41 pathogenic variants in MDS/AML patients prior to HSCT. This will allow for appropriate donor selection and donor screening.

References

  1. Li P, Brown S, Williams M, et al.: The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms. Blood 140 (7): 716-755, 2022. [PMC free article: PMC9389629] [PubMed: 35671390]
  2. Duployez N, Largeaud L, Duchmann M, et al.: Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study. Blood 140 (7): 756-768, 2022. [PMC free article: PMC9389637] [PubMed: 35443031]
  3. Alkhateeb HB, Nanaa A, Viswanatha D, et al.: Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms. Blood Adv 6 (2): 528-532, 2022. [PMC free article: PMC8791578] [PubMed: 34644397]
  4. Polprasert C, Schulze I, Sekeres MA, et al.: Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 27 (5): 658-70, 2015. [PMC free article: PMC8713504] [PubMed: 25920683]
  5. Abou Dalle I, Kantarjian H, Bannon SA, et al.: Successful lenalidomide treatment in high risk myelodysplastic syndrome with germline DDX41 mutation. Am J Hematol 95 (2): 227-229, 2020. [PubMed: 31400013]
  6. Negoro E, Radivoyevitch T, Polprasert C, et al.: Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. Leukemia 30 (12): 2405-2409, 2016. [PMC free article: PMC5143200] [PubMed: 27560106]
  7. Kobayashi S, Kobayashi A, Osawa Y, et al.: Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia 31 (4): 1020-1022, 2017. [PubMed: 28194039]
  8. Berger G, van den Berg E, Sikkema-Raddatz B, et al.: Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia 31 (2): 520-522, 2017. [PubMed: 27795557]

Latest Updates to This Summary (12/14/2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This is a new summary.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about DDX41-associated myeloid malignancies. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for DDX41-Associated Myeloid Malignancies are:

  • Julia Cooper, MS, CGC (Ohio State University)
  • Courtney DiNardo, MD, MSC (University of Texas, M.D. Anderson Cancer Center)
  • Marcin Wlodarski, MD, PhD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Cancer Genetics Editorial Board. PDQ DDX41-Associated Myeloid Malignancies. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/publications/pdq/information-summaries/genetics/ddx41-hp-pdq. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Copyright Notice
Bookshelf ID: NBK598346PMID: 38113347

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

In this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

ClearTurn OffTurn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...