文章：

结构变异塑造多发性骨髓瘤的基因组图景与临床结局

Structural variants shape the genomic landscape and clinical outcome of multiple myeloma

原文发布日期：2022-05-30

DOI: 10.1038/s41408-022-00673-x

类型: Article

开放获取: 是

英文摘要：

Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis.
 

摘要翻译： 

解读基因组结构是识别新型疾病驱动因子以及理解骨髓瘤发生与发展机制的关键。本研究利用CoMMpass数据集，揭示了结构变异（SV）在全基因组范围内以非随机方式发生：t(4;14)、RB1或TP53突变病例中SV频率增加，而t(11;14)病例中频率降低。通过将染色体重排位点映射至拓扑关联结构域，并结合RNAseq鉴定显著上调基因，我们识别了既符合预测又具有新颖性的潜在驱动基因。这些数据凸显了经典结构变异与新型结构变异共同导致转录失调的异质性。此外，研究还发现复杂重排现象（包括染色质碎裂、染色质碎裂风暴及模板化插入）在多发性骨髓瘤中普遍存在，每种变异类型具有独特的频率特征并对临床结局产生不同影响。染色质碎裂风暴与新诊断病例临床结局的独立显著负面影响相关，这支持了其与其他临床及遗传风险因素共同用于预后评估的价值。

原文链接：

Structural variants shape the genomic landscape and clinical outcome of multiple myeloma