Background: Amyloid light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibres derived from immunoglobulin that can lead to irreversible organ damage. Information about genomic profiles of AL amyloidosis is lacking.Methods: In this study, we adopted a two-step strategy to investigate the mutational profile of AL amyloidosis bone marrow plasma cells (PCs) and their clinical implications. In step one, whole-exome sequencing was performed in bone marrow PCs and paired with normal tissue from 10 AL amyloidosis patients, by which we identified 10 significantly mutated genes (SMGs). In step two, we constituted a targeted gene sequencing (TGS) panel covering the frequently mutated genes identified in step one, genes reported in prior AL amyloidosis studies, and known cancer driver mutations. Then, we analysed an expanded cohort of AL amyloidosis patients (N = 48) with this panel comprising 98 genes.Results: Four recurrent mutations were identified by TGS and verified by Sanger sequencing: ASB15 (c. 844 C > T), ASCC3 (c. 1595 A > G), HIST1H1E (c. 311 C > T) and KRAS (c. 35 G > A), among which the first three mutations were associated with inferior overall survival (OS). Additionally, we found that the number of mutations identified by the TGS panel of 98 genes could be a prognostic predictor for OS.Conclusions: In summary, we revealed genomic profiling in AL amyloidosis and found mutation profiles associated with OS.

中文翻译：

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淀粉样蛋白轻链淀粉样变性病的基因组分析揭示了与总体存活率相关的突变谱。

背景：淀粉样蛋白轻链（AL）淀粉样变性病的特征是组织沉淀源自免疫球蛋白的淀粉样蛋白纤维，可导致不可逆的器官损伤。方法：在这项研究中，我们采用了两步策略来研究AL淀粉样变性骨髓浆细胞（PCs）的突变概况及其临床意义。在第一步中，在骨髓PC中进行全外显子测序，并与10位AL淀粉样变性患者的正常组织配对，由此我们鉴定出10个显着突变的基因（SMG）。在第二步中，我们组成了靶向基因测序（TGS）面板，其中涵盖了在第一步中发现的经常突变的基因，先前的AL淀粉样变性研究中报道的基因以及已知的癌症驱动基因突变。然后，我们用这个包含98个基因的面板分析了AL淀粉样变性患者（N = 48）的扩展队列。结果：TGS鉴定了四个复发突变并通过Sanger测序验证：ASB15（c。844 C> T），ASCC3（c。 1595 A> G），HIST1H1E（c。311 C> T）和KRAS（c。35 G> A），其中前三个突变与总体生存率（OS）较低有关。此外，我们发现由TGS专家组鉴定的98个基因突变的数量可能是OS的预后指标。结论：总之，我们揭示了AL淀粉样变性的基因组图谱，并发现了与OS相关的突变谱。HIST1H1E（c。311 C> T）和KRAS（c。35 G> A），其中前三个突变与总体生存率（OS）较低有关。此外，我们发现由TGS专家组鉴定的98个基因突变的数量可能是OS的预后指标。结论：总之，我们揭示了AL淀粉样变性的基因组图谱，并发现了与OS相关的突变谱。HIST1H1E（c。311 C> T）和KRAS（c。35 G> A），其中前三个突变与总体生存率（OS）较低有关。此外，我们发现由TGS专家组鉴定的98个基因突变的数量可能是OS的预后指标。结论：总之，我们揭示了AL淀粉样变性的基因组图谱，并发现了与OS相关的突变谱。