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Development of hyperdiploidy starts at an early age and takes a decade to complete
Blood ( IF 21.0 ) Pub Date : 2024-11-26 , DOI: 10.1182/blood.2024025250
Mehmet K. Samur, Anil Aktas Samur, Parth Shah, Joseph S. Park, Mariateresa Fulciniti, Masood Shammas, Jill Corre, Kenneth C. Anderson, Giovanni Parmigiani, Hervé Avet-Loiseau, Nikhil C. Munshi

Nearly half of patients with multiple myeloma (MM) have hyperdiploidy (HMM) at diagnosis. Although HMM occurs early, the mutational processes before and after hyperdiploidy are still unclear. Here, we used 72 whole-genome sequencing samples from patients with HMM and identified pre- and post-HMM mutations to define the chronology of the development of hyperdiploidy. An MM cell accumulated a median of 0.56 mutations per mb before HMM, and for every clonal pre-HMM mutation, 1.21 mutations per mb accumulated after HMM. This analysis using mutations before and after hyperdiploidy shows that hyperdiploidy happens after somatic hypermutation. Prehyperdiploidy mutations are AID and age/clock-like signature driven, whereas posthyperdiploidy mutations are from DNA damage and APOBEC. Interestingly, the first hyperdiploidy event occurred within the first 3 decades of life and took a decade to complete. Copy number changes affecting chromosomes 15 and 19 occurred first. Finally, mutations before initiating event affected chromosomes at different rates, whereas post–initiating event mutational processes affect each chromosome equally.

中文翻译:


超二倍体的发育从很小的时候就开始了,需要十年才能完成



近一半的多发性骨髓瘤 (MM) 患者在诊断时患有高二倍体 (HMM)。尽管 HMM 发生较早,但超二倍体前后的突变过程仍不清楚。在这里,我们使用了来自 HMM 患者的 72 个全基因组测序样本,并确定了 HMM 前后突变,以定义超二倍体发展的时间顺序。MM 细胞在 HMM 之前积累的中位数为 0.56 个突变/mb,对于每个克隆的 HMM 前突变,HMM 后积累了 1.21 个突变/mb。这项使用超二倍体前后突变的分析表明,超二倍体发生在体细胞超突变之后。超二倍体前突变是 AID 和年龄/时钟样特征驱动的,而超二倍体后突变来自 DNA 损伤和 APOBEC。有趣的是,第一次超二倍体事件发生在生命的前 3 年内,花了十年时间才完成。影响 15 号和 19 号染色体的拷贝数变化首先发生。最后,事件启动前的突变以不同的速率影响染色体,而事件启动后的突变过程对每条染色体的影响相同。
更新日期:2024-11-26
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