Abstract
Clonal evolution drives tumor progression, chemoresistance and relapse in cancer. Little is known about clonal selection induced by therapeutic pressure in multiple myeloma. To address this issue, we performed large targeted sequencing of bone marrow plasma cells in 43 multiple myeloma patients at diagnosis and at relapse from exactly the same intensive treatment. The most frequently mutated genes at diagnosis were KRAS (35%), NRAS (28%), DIS3 (16%), BRAF, and LRP1B (12% each). At relapse, the mutational burden was unchanged. Many of the mutations were present at the subclonal level at both time points, including driver ones. According to patients and mutations, we observed different scenarios: selection of a very rare subclone present at diagnosis, appearance, or disappearance of mutations, but also stability. Our data highlight that chemoresistance and relapse could be induced by newly acquired mutations in myeloma drivers but also by (sub)clonal mutations preexisting to the treatment. Importantly, no specific mutation or rearrangement was observed at relapse, demonstrating that intensive treatment has a nonspecific effect on clonal selection in multiple myeloma. Finally, we identified 22 cases of biallelic event, including a double event deletion 17p/TP53mut.
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Acknowledgements
This work was supported by NIH grants PO1-155258 and P50-100707 (NM, HAL); Department of Veterans Affairs Merit Review Award 1 I01BX001584-01 (NM) and the CAPTOR program. The CRCT Team 13 is labeled by ARC. We thank the Intergroupe Francophone du Myelome for providing patient samples and clinical data.
Author contributions
JC, AC, NM, and HAL conceived the project, JC, AC, SR, and HAL analyzed the data, AC performed bioinformatics analysis, LB performed experiments, NB conceived the sequencing targeted panel, MA provided samples and clinical data, AC, JC, NM, and HAL wrote the manuscript which was reviewed and edited by the other co-authors.
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NB received honoraria and personal fees from Celgene Corporation. The remaining authors declare that they have no conflict of interest.
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Corre, J., Cleynen, A., Robiou du Pont, S. et al. Multiple myeloma clonal evolution in homogeneously treated patients. Leukemia 32, 2636–2647 (2018). https://doi.org/10.1038/s41375-018-0153-6
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DOI: https://doi.org/10.1038/s41375-018-0153-6
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