Rustad, Even H.Yellapantula, VenkataLeongamornlert, DanielBolli, NiccolòLedergor, GuyNadeu Prat, FerranAngelopoulos, NicosDawson, Kevin J.Mitchell, Thomas J.Osborne, Robert J.Ziccheddu, BachisioCarniti, CristianaMontefusco, VittorioCorradini, PaoloAnderson, Kenneth C.Moreau, PhilippePapaemmanuil, ElliAlexandrov, Ludmil B.Puente, Xose S.Campo Güerri, EliasSiebert, ReinerAvet-Loiseau, HervéLandgren, OlaMunshi, NikhilCampbell, Peter J.Maura, Francesco2021-07-062021-07-062020-04-212041-1723https://hdl.handle.net/2445/178864The 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 2nd-3rd 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 premalignant 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.14 p.application/pdfengcc-by (c) Rustad, Even H. et al., 2020https://creativecommons.org/licenses/by/4.0/Mieloma múltipleEtiologiaMultiple myelomaEtiologyinfo:eu-repo/semantics/article7014932021-07-06info:eu-repo/semantics/openAccess32317634