文章：

一种用于复发性IGH易位多发性骨髓瘤进化动态的增强遗传模型

An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics

原文发布日期：2020-10-14

DOI: 10.1038/s41408-020-00367-2

类型: Article

开放获取: 是

英文摘要：

Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of “evolutionary herding” approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.
 

摘要翻译： 

大多数多发性骨髓瘤（MM）患者在疾病复发后死于病情进展。为深入理解MM的演化机制，我们对骨髓瘤XI试验中80对IGH易位的新发肿瘤-正常组织样本及24个匹配的复发肿瘤进行了全基因组测序。研究发现多种事件可能对复发后的生存和治疗耐药性具有重要影响，包括驱动点突变（如TET2）、染色体易位（MAP3K14）、端粒延长以及基因组不稳定性增加（如17p缺失）。尽管不同MM亚型中导致复发突变的突变过程存在异质性，但AID/APOBEC活性的增强与较短复发进展时间显著相关，并导致复发时突变负荷升高。此外，我们发现了三种强化的MM复发主要克隆进化模式，这些模式与治疗策略和分子核型无关，这对“进化聚集”方法治疗耐药性MM的可行性提出了质疑。我们的数据表明MM复发与新突变获取和克隆选择相关，并提示APOBEC酶可能成为治疗耐药性MM的潜在靶点。

原文链接：

An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics