Department of Pathology and Laboratory Medicine and.
Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
Blood. 2022 Feb 24;139(8):1208-1221. doi: 10.1182/blood.2021011354.
Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.
遗传性髓系恶性肿瘤的易感性比以前认为的更为常见。我们分析了来自 Beat AML 1.0 联盟的 391 名成年患者配对白血病和皮肤活检样本的全外显子组测序数据。使用 2015 年美国医学遗传学与基因组学学会（ACMG）的变异解释指南，我们从 228 个基因中筛选出 1547 个独特的变异。在 34 个基因中，有 53 名急性髓系白血病（AML）患者（13.6%）确定了致病性/可能致病性（P/LP）种系变异，其中 6.39%（25/391）的患者携带了临床可操作（1 级）基因的 P/LP 变异。53 名 P/LP 变异患者中有 41.5%的变异与 DNA 损伤反应相关基因有关。最常突变的基因是 CHEK2（8 例）和 DDX41（7 例）。致病性种系变异也存在于新的候选基因（DNAH5、DNAH9、DNMT3A 和 SUZ12）中。种系突变率与 AML 发病年龄之间没有很强的相关性。在 49 名有至少一名家族成员患有血液系统恶性肿瘤病史的患者中，6 名患者携带已知的 P/LP 种系变异，其余患者至少有一个意义不明的变异，表明需要进一步进行功能验证研究。以 CHEK2 为例，我们展示了三维蛋白质建模可以是一种有效的方法，用于对功能研究中未知意义的变异进行优先级排序。此外，我们评估了一种基于计算机的方法，该方法使用用于评估和（TAPES）优先排序的工具以自动化方式应用 ACMG 编辑，这可以最大限度地减少变异的手动编辑时间。总体而言，我们的研究结果表明，需要全面了解许多种系变异的易感性潜力，以便能够更密切地监测疾病管理和治疗干预，以针对受影响的患者及其家属。
