Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Hematology, The First People's Hospital of Yancheng, Yancheng Affiliated Hospital of Xuzhou Medical University, The Fourth Affiliated Hospital of Nantong University, Yancheng, China.
Cancer. 2021 Jun 15;127(12):2039-2048. doi: 10.1002/cncr.33454. Epub 2021 Mar 25.
Waldenström macroglobulinemia (WM) is a rare chronic B-cell lymphoma. Familial clustering of WM has been observed over the years. However, little is known about the contribution of inherited genetic variants to familial WM cases.
The authors performed whole exome sequencing (WES) of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Bioinformatics analysis of public biological databases was used to identify the most relevant familial WM candidate from WES. Transcript expression and protein levels of the familial WM candidate were evaluated in the WM patient and 2 unaffected members of the kindred.
Among the 10 shared candidate mutations in the twins, the authors identified a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) as a familial WM-associated mutation. FHL2 appeared to be connected with reported signaling pathways and disease-driving genes such as IL6 and HCK in WM. In addition, the authors found reduced FHL2 messenger RNA and protein expression in peripheral blood samples from the patient with WM in comparison with the healthy siblings.
Taken together, these findings indicate that an FHL2 mutation may play an important role in familial WM, and they provide new screening possibilities for familial cases.
Familial clustering in Waldenström macroglobulinemia (WM) has been observed over the years. The authors performed whole exome sequencing of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Among the 10 shared candidate mutations in the twins, a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) was identified as the most relevant familial WM candidate through bioinformatics analysis of a public database. Also, messenger RNA and protein expression of FHL2 was significantly lower in peripheral blood mononuclear cells of the WM patient in comparison with the healthy siblings, and this suggested that the function of FHL2 was impaired when mutated.
华氏巨球蛋白血症（WM）是一种罕见的慢性 B 细胞淋巴瘤。多年来，人们观察到 WM 存在家族聚集现象。然而，对于遗传变异在家族性 WM 病例中的作用知之甚少。
作者对一对双胞胎的胚系 DNA 样本进行了全外显子组测序（WES），其中一个被诊断为 WM，另一个被诊断为免疫球蛋白 M 单克隆丙种球蛋白血症，且其健康的兄弟姐妹也参与了该研究。作者利用公共生物数据库的生物信息学分析，从 WES 中确定了与家族性 WM 最相关的候选基因。作者还评估了家族性 WM 候选基因在 WM 患者和家族中另外 2 位未受影响成员的转录表达和蛋白水平。
在双胞胎的 10 个共享候选突变中，作者发现了一个新的杂合胚系突变，即四个半 LIM 结构域蛋白 2（FHL2；c.G226A，p.V76M），这是一个与家族性 WM 相关的突变。FHL2 似乎与 WM 中报告的信号通路和疾病驱动基因（如 IL6 和 HCK）有关。此外，作者发现 WM 患者外周血样本中的 FHL2 信使 RNA 和蛋白表达水平较健康兄弟姐妹明显降低。
综上所述，这些发现表明 FHL2 突变可能在家族性 WM 中发挥重要作用，并为家族性病例提供了新的筛查可能性。
多年来，人们观察到华氏巨球蛋白血症（WM）存在家族聚集现象。作者对一对双胞胎的胚系 DNA 样本进行了全外显子组测序（WES），其中一个被诊断为 WM，另一个被诊断为免疫球蛋白 M 单克隆丙种球蛋白血症，且其健康的兄弟姐妹也参与了该研究。在双胞胎的 10 个共享候选突变中，作者通过公共数据库的生物信息学分析，确定了一个新的杂合胚系突变，即四个半 LIM 结构域蛋白 2（FHL2；c.G226A，p.V76M），这是与家族性 WM 最相关的候选基因。此外，WM 患者外周血单核细胞中的 FHL2 信使 RNA 和蛋白表达水平明显低于健康兄弟姐妹，这表明 FHL2 发生突变时其功能受损。
