期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-15740-9
关键词
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资金
- Memorial Sloan Kettering Cancer Center NCI Core Grant [P30 CA008748]
- Instituto de Salud Carlos III [PMP15/00007]
- la Caixa Foundation [HR17-00221]
- Ministerio de Economia y Competitividad (MINECO) from Plan Nacional de I+D+I, Generalitat de Catalunya Suport Grups de Recerca [SAF2013-45836-R, AGAUR 2017-SGR-1142]
- European Regional Development Fund Una manera de hacer Europa, Department of Veterans Affairs Merit Review Award [I01BX001584-01]
- NIH [P01-155258, 5P50CA100707-13]
- International Myeloma Society (IMS)
- American Society of Hematology
- International Myeloma Foundation
- Society of Memorial Sloan Kettering Cancer Center
- University of Milan [22597 - PSR2017_DIP_032]
- European Research Council under the European Union's Horizon 2020 research and innovation programme [817997]
- Ministerio de Economia y Competitividad [SAF2017-87811-R]
- MINECO [BES-2016-076372]
- ICREA under the ICREA Academia programme
- BMBF [FKZ 01KU1002A, 01KU1505, 031A428H]
The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2(nd)-3(rd) decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection. The initial mutational processes and how these lead to progression in multiple myeloma (MM) are unclear. Here, the authors identify mutational signatures that occur over time in a large cohort of MM patients and suggest features that may help in early diagnosis.
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