Division of Hematology-Oncology and Bone Marrow Transplant Program, Mayo Clinic, Jacksonville, FL 32224.
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; John H. Stroger, Jr. Hospital of Cook County, Chicago, IL 60612.
Haematologica. 2023 Nov 1;108(11):3033-3043. doi: 10.3324/haematol.2023.282867.
The diagnosis of germline predisposition to myeloid neoplasms (MN) secondary to DDX41 variants is currently hindered by the long latency period, variable family histories and the frequent occurrence of DDX41 variants of uncertain significance (VUS). We reviewed 4,524 consecutive patients who underwent targeted sequencing for suspected or known MN and analyzed the clinical impact and relevance of DDX41VUS in comparison to DDX41path variants. Among 107 patients (44 [0.9%] DDX41path and 63 DDX41VUS [1.4%; 11 patients with both DDX41path and DDX41VUS]), we identified 17 unique DDX41path and 45 DDX41VUS variants: 24 (23%) and 77 (72%) patients had proven and presumed germline DDX41 variants, respectively. The median age was similar between DDX41path and DDX41VUS (66 vs. 62 years; P=0.41). The median variant allele frequency (VAF) (47% vs. 48%; P=0.62), frequency of somatic myeloid co-mutations (34% vs 25%; P= 0.28), cytogenetic abnormalities (16% vs. 12%; P=>0.99) and family history of hematological malignancies (20% vs. 33%; P=0.59) were comparable between the two groups. Time to treatment in months (1.53 vs. 0.3; P=0.16) and proportion of patients progressing to acute myeloid leukemia (14% vs. 11%; P=0.68), were similar. The median overall survival in patients with high-risk myelodysplastic syndrome/acute myloid leukemia was 63.4 and 55.7 months in the context of DDX41path and DDX41VUS, respectively (P=0.93). Comparable molecular profiles and clinical outcomes among DDX41path and DDX41VUS patients highlights the need for a comprehensive DDX41 variant interrogation/classification system, to improve surveillance and management strategies in patients and families with germline DDX41 predisposition syndromes.
由于胚系易感性骨髓增生性肿瘤（MN）的潜伏期长、家族史多变以及 DDX41 意义不明变异体（VUS）的频繁发生，目前对其的诊断受到阻碍。我们回顾了 4524 例连续接受疑似或已知 MN 靶向测序的患者，并分析了 DDX41VUS 与 DDX41 致病性变异体相比的临床影响和相关性。在 107 例患者（44 例 DDX41 致病性变异体[0.9%]和 63 例 DDX41VUS [1.4%；11 例同时存在 DDX41 致病性变异体和 DDX41VUS]）中，我们鉴定了 17 个独特的 DDX41 致病性变异体和 45 个 DDX41VUS 变异体：分别有 24 例（23%）和 77 例（72%）患者存在明确和假定的胚系 DDX41 变异体。DDX41 致病性变异体和 DDX41VUS 患者的中位年龄相似（66 岁比 62 岁；P=0.41）。变异等位基因频率（VAF）（47%比 48%；P=0.62）、体细胞髓系共突变频率（34%比 25%；P=0.28）、细胞遗传学异常（16%比 12%；P=0.99）和血液系统恶性肿瘤家族史（20%比 33%；P=0.59）在两组间也无差异。两组间治疗开始的时间（1.53 个月比 0.3 个月；P=0.16）和进展为急性髓系白血病的患者比例（14%比 11%；P=0.68）也相似。高危骨髓增生异常综合征/急性髓系白血病患者的中位总生存期分别为 DDX41 致病性变异体和 DDX41VUS 背景下的 63.4 个月和 55.7 个月（P=0.93）。DDX41 致病性变异体和 DDX41VUS 患者的分子谱和临床结局相似，这突出表明需要建立一个全面的 DDX41 变异体检测/分类系统，以改善胚系 DDX41 易感性综合征患者及其家属的监测和管理策略。
