Tierens Anne, Kagotho Elizabeth, Shinriki Satoru, Seto Andrew, Smith Adam C, Care Melanie, Maze Dawn, Sibai Hassan, Yee Karen W, Schuh Andre C, Kim Dennis Dong Hwan, Gupta Vikas, Minden Mark D, Matsui Hirotaka, Capo-Chichi José-Mario
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Nairobi, Kenya.
Front Oncol. 2023 Jun 26;13:1153082. doi: 10.3389/fonc.2023.1153082. eCollection 2023.
Inherited mutations cause familial predisposition to hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with the majority of DDX41 mutated MDS/AMLs described to date harboring germline and co-occurring somatic variants. DDX41-AMLs were shown to share distinguishing clinical features such as a late AML onset and an indolent disease associated with a favorable outcome. However, genotype-phenotype correlation in DDX41-MDS/AMLs remain poorly understood.
Here, we studied the genetic profile, bone marrow morphology and immunophenotype of 51 patients with DDX41 mutations. We further assessed the functional impact of ten previously uncharacterized variants of uncertain significance.
Our results demonstrate that MDS/AML cases harboring two variants share specific clinicopathologic hallmarks that are not seen in other patients with monoallelic related hematologic malignancies. We further showed that the features seen in these individuals with two variants were concordant with biallelic disruption.
Here, we expand on previous clinicopathologic findings on mutated hematologic malignancies. Functional analyses conducted in this study unraveled previously uncharacterized alleles and further illustrate the implication of biallelic disruption in the pathophysiology of this distinct AML entity.
遗传性突变导致家族性易患血液系统恶性肿瘤，包括急性髓系白血病（AML）和骨髓增生异常综合征（MDS），迄今为止描述的大多数DDX41突变的MDS/AML都存在种系和同时发生的体细胞变异。DDX41-AML被证明具有一些独特的临床特征，如AML发病较晚以及与良好预后相关的惰性疾病。然而，DDX41-MDS/AML中的基因型-表型相关性仍知之甚少。
在此，我们研究了51例DDX41突变患者的基因谱、骨髓形态和免疫表型。我们进一步评估了10个先前未鉴定的意义未明变异的功能影响。
我们的结果表明，携带两个变异的MDS/AML病例具有特定的临床病理特征，而在其他单等位基因相关血液系统恶性肿瘤患者中未见这些特征。我们进一步表明，这些携带两个变异的个体中所见的特征与双等位基因破坏一致。
在此，我们扩展了先前关于突变血液系统恶性肿瘤的临床病理研究结果。本研究中进行的功能分析揭示了先前未鉴定的等位基因，并进一步阐明了双等位基因破坏在这种独特AML实体病理生理学中的意义。
