The genetic landscape of germline<i>DDX41</i>variants predisposing to myeloid neoplasms

  • Peng Li
    1Division of Hematopathology, Department of Pathology, University of Utah Health, Salt Lake City, UT;
  • Sara Brown
    2Genomics Laboratory, ARUP Laboratories, Salt Lake City, UT;
  • Margaret Williams
    1Division of Hematopathology, Department of Pathology, University of Utah Health, Salt Lake City, UT;
  • Thomas White
    2Genomics Laboratory, ARUP Laboratories, Salt Lake City, UT;
  • Wei Xie
    3Department of Pathology, School of Medicine, Oregon Health and Science University, Portland, OR;
  • Wei Cui
    4Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS;
  • Deniz Peker
    5Division of Hematopathology, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA;
  • Li Lei
    6Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA;
  • Christian A. Kunder
    7Department of Pathology, Stanford University, School of Medicine, Stanford, CA;
  • Huan-You Wang
    8Department of Pathology & Immunology, University of California San Diego Health System, La Jolla, CA;
  • Sarah S. Murray
    8Department of Pathology & Immunology, University of California San Diego Health System, La Jolla, CA;
  • Jennie Vagher
    9Department of Internal Medicine, University of Utah Health, Salt Lake City, UT; and
  • Tibor Kovacsovics
    9Department of Internal Medicine, University of Utah Health, Salt Lake City, UT; and
  • Jay L. Patel
    1Division of Hematopathology, Department of Pathology, University of Utah Health, Salt Lake City, UT;

抄録

<jats:title>Abstract</jats:title><jats:p>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 &lt; .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.</jats:p>

収録刊行物

  • Blood

    Blood 140 (7), 716-755, 2022-08-18

    American Society of Hematology

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