Maura Francesco, Kaddoura Marcella, Poos Alexandra M, Baughn Linda B, Ziccheddu Bachisio, Bärtsch Marc-Andrea, Cirrincione Anthony, Maclachlan Kylee, Chojnacka Monika, Diamond Benjamin, Papadimitriou Marios, Blaney Patrick, John Lukas, Reichert Philipp, Huhn Stefanie, Gagler Dylan, Zhang Yanming, Dogan Ahmet, Lesokhin Alexander M, Davies Faith, Goldschmidt Hartmut, Fenk Roland, Weisel Katja C, Mai Elias K, Korde Neha, Morgan Gareth J, Rajkumar S Vincent, Kumar Shaji, Usmani Saad, Landgren Ola, Raab Marc S, Weinhold Niels
Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
Nat Genet. 2025 Aug 20. doi: 10.1038/s41588-025-02292-1.
Multiple myeloma evolution is characterized by the accumulation of genomic drivers over time. To unravel this timeline and its impact on clinical outcomes, we analyzed 421 whole-genome sequences from 382 patients. Using clock-like mutational signatures, we estimated a time lag of two to four decades between the initiation of events and diagnosis. We demonstrate that odd-numbered chromosome trisomies in patients with hyperdiploidy can be acquired simultaneously with other chromosomal gains (for example, 1q gain). We show that hyperdiploidy is acquired after immunoglobulin heavy chain translocation when both events co-occur. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra copy), but fared worse than those with late 1q gain. This finding underscores that the 1q gain prognostic impact depends more on the timing of acquisition than on the number of copies gained. Overall, this study contributes to a better understanding of the life history of myeloma and may have prognostic implications.
多发性骨髓瘤的演变特征是随着时间推移基因组驱动因素不断积累。为了理清这一时间线及其对临床结果的影响，我们分析了382例患者的421个全基因组序列。利用类似时钟的突变特征，我们估计事件起始与诊断之间存在两到四十年的时间间隔。我们证明，超二倍体患者的奇数染色体三体可与其他染色体增加（例如1q增加）同时获得。我们表明，当免疫球蛋白重链易位与超二倍体同时发生时，超二倍体是在免疫球蛋白重链易位之后获得的。最后，早期发生1q增加的患者的不良预后与1q扩增（额外拷贝数>1）的患者相似，但比晚期发生1q增加的患者预后更差。这一发现强调，1q增加的预后影响更多地取决于获得的时间而非获得的拷贝数。总体而言，本研究有助于更好地理解骨髓瘤的生命历程，可能具有预后意义。
