Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK.
Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, UK.
Blood Cancer J. 2020 Oct 14;10(10):101. doi: 10.1038/s41408-020-00367-2.
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.
大多数多发性骨髓瘤（MM）患者在复发后因疾病进展而死亡。为了深入了解 MM 的进化机制，我们对 Myeloma XI 试验中的 80 对IGH 易位肿瘤-正常新诊断配对和 24 对匹配的复发肿瘤进行了全基因组测序。我们确定了多个潜在重要的事件，包括驱动点突变（如 TET2）、易位（MAP3K14）、端粒延长和基因组不稳定性增加（如 17p 缺失），这些都与复发时的生存和耐药性有关。尽管在 MM 亚型中，导致复发突变的突变过程存在异质性，但 AID/APOBEC 活性的增加与复发的进展时间更短尤其相关，并导致复发时更高的突变负担。此外，我们发现了三种独立于治疗策略和分子核型的 MM 复发的增强主要克隆进化模式，这对治疗耐药性 MM 的“进化趋同”方法提出了质疑。我们的数据表明，MM 复发与新突变的获得和克隆选择有关，并提示 APOBEC 酶可能是治疗耐药性 MM 的潜在靶点。
