新发多发性骨髓瘤中罕见结构变异事件的影响。
Impact of Rare Structural Variant Events in Newly Diagnosed Multiple Myeloma.
机构信息
Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
出版信息
Clin Cancer Res. 2024 Feb 1;30(3):575-585. doi: 10.1158/1078-0432.CCR-23-1045.
PURPOSE
Whole-genome sequencing (WGS) of patients with newly diagnosed multiple myeloma (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e., hotspots) and causing recurrent copy-number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as "recurrent SVs." More than half of SVs were not involved in recurrent events. The significance of these "rare SVs" has not been previously examined.
EXPERIMENTAL DESIGN
In this study, we utilize 752 WGS and 591 RNA sequencing data from patients with NDMM to determine the role of rare SVs in myeloma pathogenesis.
RESULTS
Ninety-four percent of patients harbored at least one rare SV event. Rare SVs showed an SV class-specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs.
CONCLUSIONS
Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a potential driver role in myeloma pathogenesis.
目的
对新诊断多发性骨髓瘤（NDMM）患者进行全基因组测序（WGS），结果显示基因组中特定区域（即热点）的结构变异（SV）反复出现，并导致反复的拷贝数改变。这些 SV 与典型的免疫球蛋白易位一起，被认为是“反复出现的 SV”。超过一半的 SV 不涉及反复出现的事件。这些“罕见 SV”的意义以前没有被研究过。
实验设计
在这项研究中，我们利用 752 例 NDMM 患者的 WGS 和 591 例 RNA 测序数据，确定罕见 SV 在骨髓瘤发病机制中的作用。
结果
94%的患者至少存在一个罕见 SV 事件。罕见 SV 在与异常基因表达相关的基因和超级增强子中表现出 SV 类特异性富集。此外，已知受点突变反复影响的骨髓瘤驱动基因也受到罕见 SV 的调控失常。
结论
总的来说，我们证明了罕见 SV 与异常基因表达相关，支持其在骨髓瘤发病机制中具有潜在驱动作用。
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