Germline mutations in DDX41 may increase a patient’s lifetime risk of late-onset myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Identification of this germline mutation leads to more timely and appropriate care for patients with myeloid neoplasms, according to a study. Sarah Bannon, MS, of the University of Texas MD Anderson Cancer Center in Houston, discussed the findings at the ASH Annual Meeting on December 2, 2018.

Researchers performed next-generation sequencing (NGS) of DDX41 in 1,262 patients with myeloid malignancies. Patients with one or more DDX41 alterations present at greater than 40% variant allele frequency in the bone marrow were referred for genetic counseling and could undergo DDX41 germline analysis on cultured skin fibroblasts.

In that cohort, 32 patients (2.5%) had one or more somatic DDX41 mutations, and 14 (44%) underwent germline confirmation testing. Most patients were male (n = 11; 78.5%) and Caucasian (n = 13; 93%). The average age at diagnosis was 65 years (range = 53–77 years): eight patients had AML and six had MDS. Twelve patients presented with diploid cytogenetics.

Many patients (71%) had a second somatic DDX41 mutation. The researchers observed no other significantly recurrent concomitant somatic mutations. Thirteen patients underwent germline evaluation, and 12 (92%) had confirmed germline DDX41 mutation.

Six individuals underwent hematopoietic cell transplantation (HCT): five had a matched donor, and in four cases, related donor was DDX41-negative. Six patients (43%) reported antecedent cytopenias, including five with leukopenia and one with anemia.

Five patients had a prior history of malignancy, including prostate cancer (n = 3), non-Hodgkin lymphoma and melanoma (n = 1), and monoclonal gammopathy of undetermined significance (n = 1).

Thirteen patients (93%) had a family history of cancer, six (43%) of which were hematologic malignancies. Eleven relatives of 12 DDX41 germline-positive patients underwent genetic testing, and four (36%) tested positive for the familial DDX41 mutation.

“The detection of somatic DDX41 mutations at near-heterozygous frequencies on NGS panel testing is highly suggestive of a germline mutation, and germline testing is strongly recommended,” the authors concluded.