Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing

Li Ding, Timothy Ley, David E. Larson, Christopher Miller, Daniel C. Koboldt, John Welch, Julie K. Ritchey, Margaret A. Young, Tamara Lamprecht, Michael D. McLellan, Joshua F. McMichael, John W. Wallis, Charles Lu, Dong Shen, Christopher C. Harris, David J. Dooling, Robert Fulton, Lucinda L. Fulton, Ken Chen, Heather SchmidtJoelle Kalicki-Veizer, Vincent J. Magrini, Lisa Cook, Sean D. McGrath, Tammi L. Vickery, Michael Wendl, Sharon Heath, Mark Watson, Daniel Link, Michael H. Tomasson, William D. Shannon, Jacqueline Payton, Shashikant Kulkarni, Peter Westervelt, Matthew Walter, Timothy A. Graubert, Elaine R. Mardis, Richard K. Wilson, John Dipersio

Research output: Contribution to journalArticle

1252 Scopus citations

Abstract

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.

Original languageEnglish
Pages (from-to)506-510
Number of pages5
JournalNature
Volume481
Issue number7382
DOIs
StatePublished - Jan 26 2012

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    Ding, L., Ley, T., Larson, D. E., Miller, C., Koboldt, D. C., Welch, J., Ritchey, J. K., Young, M. A., Lamprecht, T., McLellan, M. D., McMichael, J. F., Wallis, J. W., Lu, C., Shen, D., Harris, C. C., Dooling, D. J., Fulton, R., Fulton, L. L., Chen, K., ... Dipersio, J. (2012). Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature, 481(7382), 506-510. https://doi.org/10.1038/nature10738