The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms

• Type of Material: Article
• Authors: Peng Li, University of Utah Health; Sara Brown, ARUP Laboratories; Margaret Williams, University of Utah Health; Thomas White, ARUP Laboratories; Wei Xie, Oregon Health and Science University; Wei Cui, University of Kansas; Deniz Peker, Emory University; Li Lei, University of California Davis; Christain A. Kunder, Stanford University; Huan-You Wang, University of California San Diego; Sarah S. Murray, University of California San Diego; Jennie Vagher, University of Utah Health; Tibor Kovacsovics, University of Utah Health; Jay L. Patel, University of Utah Health
• Language: English
• Date: 2022-08-18
• Publisher: AMER SOC HEMATOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by The American Society of Hematology
• Final Published Version (URL): http://dx.doi.org/10.1182/blood.2021015135
• Title of Journal or Parent Work: BLOOD
• Volume: 140
• Issue: 7
• Start Page: 716
• End Page: 755
• Keywords: LEUKEMIA; FAMILY; MUTATIONS; Life Sciences & Biomedicine; COHORT; Hematology; CANCER; Science & Technology
• Research Categories: Health Sciences, Oncology; Biology, Genetics

Abstract

Germline DDX41 variants are the most common mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults, but the causal variant (CV) landscape and clinical spectrum of hematologic malignancies (HMs) remain unexplored. Here, we analyzed the genomic profiles of 176 patients with HM carrying 82 distinct presumably germline DDX41 variants among a group of 9821 unrelated patients. Using our proposed DDX41-specific variant classification, we identified features distinguishing 116 patients with HM with CV from 60 patients with HM with variant of uncertain significance (VUS): an older age (median 69 years), male predominance (74% in CV vs 60% in VUS, P = .03), frequent concurrent somatic DDX41 variants (79% in CV vs 5% in VUS, P < .0001), a lower somatic mutation burden (1.4 ± 0.1 in CV vs 2.9 ± 0.04 in VUS, P = .012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBPA, and FLT3 in AML, and favorable overall survival (OS) in patients with AML/MDS. This superior OS was determined independent of blast count, abnormal karyotypes, and concurrent variants, including TP53 in patients with AML/MDS, regardless of patient's sex, age, or specific germline CV, suggesting that germline DDX41 variants define a distinct clinical entity. Furthermore, unrelated patients with myeloproliferative neoplasm and B-cell lymphoma were linked by DDX41 CV, thus expanding the known disease spectrum. This study outlines the CV landscape, expands the phenotypic spectrum in unrelated DDX41-mutated patients, and underscores the urgent need for gene-specific diagnostic and clinical management guidelines.