Germline DDX41 mutations define a significant entity within adult MDS/AML patients

Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequenc...

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Published in:	Blood 2019-10, Vol.134 (17), p.1441-1444
Main Authors:	Sébert, Marie, Passet, Marie, Raimbault, Anna, Rahmé, Ramy, Raffoux, Emmanuel, Sicre de Fontbrune, Flore, Cerrano, Marco, Quentin, Samuel, Vasquez, Nadia, Da Costa, Mélanie, Boissel, Nicolas, Dombret, Hervé, Peffault de Latour, Régis, Socié, Gérard, Itzykson, Raphaël, Fenaux, Pierre, Soulier, Jean, Adès, Lionel, Clappier, Emmanuelle
Format:	Article
Language:	eng
Subjects:	Adult Aged Aged, 80 and over Cohort Studies DEAD-box RNA Helicases - genetics Female Germ-Line Mutation Humans Leukemia, Myeloid, Acute - genetics Male Middle Aged Myelodysplastic Syndromes - genetics
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Summary:	Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients, which we classified as causal (n = 21) or unknown significance (n = 7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. The median age was 69 years; most patients were men (79%). Only 9 patients (27%) had a family history of hematological malignancy, and 15 (46%) had a personal history of cytopenia years before MDS/AML diagnosis. Most patients had a normal karyotype (85%), and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n = 9) or azacitidine (n = 11) had an overall response rate of 100% or 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome. •Germline DDX41 mutations are found in a significant proportion of sporadic MDS/AML patients.•Patients with DDX41-related MDS/AML have a relatively favorable outcome. [Display omitted]
ISSN:	0006-4971 1528-0020