Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.

Insights into DDX41 MDS/AML predisposing gene variants

January 2024—DDX41 is involved in multiple cellular processes, including RNA metabolism and splicing. Inherited variants have been linked to an increased risk of the blood neoplasms myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Unlike people with other hereditary hematologic malignancy-associated genes, people with DDX41 germline pathogenic variants are predisposed to develop late-onset myeloid neoplasms. Recent reports suggest that people who have AML with DDX41 mutation have longer overall survival and a higher treatment response rate than those with DDX41 wild-type AML and favorable-risk AML. Small retrospective studies also suggested that DDX41-mutated AML is more sensitive to treatment with Venetoclax plus hypomethylating agents than is sporadic AML. A recent article in Blood (Kovilakam SC, et al. 2023;​142:1185–1192) detailed a comprehensive population-level analysis of 454,792 adult participants in the UK Biobank. The analysis assessed the epidemiologic characteristics, clinical features, and malignancy risk associated with germline pathogenic variants in DDX41. The authors found that approximately one in 129 people from their data set carried a nonsynonymous germline variant in DDX41 and approximately one in 429 had a pathogenic variant. Of the 3,538 DDX41 pathogenic variant carriers, 25 developed MDS and 20 developed AML after initial sample collection. The median age at MDS/AML onset was 71 years. The variants among the 45 people who developed MDS/AML were truncating (n=21), start-lost (n=7), missense (n=16), and splice site (n=1). Using logistic regression with age, gender, smoking status, and genetic ethnicity as covariates, the authors found that the odds ratios for developing MDS/AML were 15.12, 12.89, and 7.49, respectively, for truncating, start-lost, and pathogenic missense variants. The rare variant R53Afs*16 was found to impart a very high risk, with four of 16 carriers developing MDS/AML, compared with more common pathogenic variants, such as D140Gfs*2 and start-lost. The authors also investigated possible links between DDX41 variants and myeloproliferative neoplasms, lymphomas, and other cancers but did not find significant associations. Looking for other hallmarks of myeloid disease development, the authors investigated blood count results for the 32 people with available data who developed AML or MDS after initial sampling. They found that mean red cell volume was higher in these people than in DDX41 pathogenic variant carriers who did not develop MDS/AML. Their data also showed that DDX41-mutated MDS/AML did not generally develop through progression from clonal hematopoiesis. Links between DEAD-box RNA helicases and genomic stability have been reported, but the authors did not find significant differences in somatic mutation rates between DDX41-mutant AML patients and sporadic AML patients. Overall, the authors provided a comprehensive description of DDX41 mutations from their large data set. While DDX41 pathogenic variants were relatively common in this study population, the absolute risk of DDX41 pathogenic carriers developing MDS/AML was 3.21 percent (5.50 percent in males and 1.37 percent in females), which is lower than estimates derived from prior studies of the relatives of DDX41-mutated MDS/AML patients.

Kovilakam SC, Gu M, Dunn WG, et al. Prevalence and significance of DDX41 gene variants in the general population. Blood. 2023;142(14):1185–1192.

Correspondence: Dr. George S. Vassiliou at gsv20@cam.ac.uk

Nanaa A, He R, Foran JM, et al. Venetoclax plus hypomethylating agents in DDX41-mutated acute myeloid leukaemia and myelodysplastic syndrome: Mayo Clinic series on 12 patients. Br J Haematol. 2023. doi:10.1111/bjh.19105

Correspondence: Dr. Hassan Alkhateeb at alkhateeb.hassan@mayo.edu